U.S. patent application number 10/809946 was filed with the patent office on 2005-01-06 for thiazoles useful as inhibitors of protein kinases.
Invention is credited to Brenchley, Guy, Farmer, Luc J., Harrington, Edmund M., Knegtel, Ronald, O'Donnell, Michael, Salituro, Francesco G., Studley, John R., Wang, Jian.
Application Number | 20050004150 10/809946 |
Document ID | / |
Family ID | 33131687 |
Filed Date | 2005-01-06 |
United States Patent
Application |
20050004150 |
Kind Code |
A1 |
Brenchley, Guy ; et
al. |
January 6, 2005 |
Thiazoles useful as inhibitors of protein kinases
Abstract
The present invention relates to compounds useful of inhibitors
of protein kinases. The invention also provides pharmaceutically
acceptable compositions comprising said compounds and methods of
using the compositions in the treatment of various disease,
conditions, or disorders.
Inventors: |
Brenchley, Guy; (Grove
Wantage, GB) ; Farmer, Luc J.; (Foxboro, MA) ;
Harrington, Edmund M.; (Plymouth, MA) ; Knegtel,
Ronald; (Abingdon, GB) ; O'Donnell, Michael;
(Abingdon, GB) ; Salituro, Francesco G.;
(Marlboro, MA) ; Studley, John R.; (Abingdon,
GB) ; Wang, Jian; (Newton, MA) |
Correspondence
Address: |
VERTEX PHARMACEUTICALS INC.
130 WAVERLY STREET
CAMBRIDGE
MA
02139-4242
US
|
Family ID: |
33131687 |
Appl. No.: |
10/809946 |
Filed: |
March 25, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60457468 |
Mar 25, 2003 |
|
|
|
Current U.S.
Class: |
514/275 ;
544/331 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 417/14 20130101; A61P 37/08 20180101; A61P 37/06 20180101;
A61P 43/00 20180101; C07D 417/04 20130101; A61P 11/00 20180101;
A61P 37/04 20180101; A61P 29/00 20180101; A61P 11/06 20180101; A61P
37/00 20180101 |
Class at
Publication: |
514/275 ;
544/331 |
International
Class: |
A61K 031/506; C07D
417/04 |
Claims
1. A compound of formula (I): 132or a pharmaceutically acceptable
salt thereof, wherein: R.sup.1 and R.sup.2 are each independently
R, halogen, CN, NO.sub.2, or TR, or R.sup.1 and R.sup.2 taken
together form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3
heteroatoms independently selected from N, O, or S; T is an
optionally substituted C.sub.1-C.sub.4 alkylidene chain wherein up
to two methylene units of T are optionally and independently
replaced by O, N(R'), C(O), S, SO, or SO.sub.2; Ar.sup.1 is an
optionally substituted ring selected from: an aryl group selected
from a 5-6 membered monocyclic or an 8-10 membered bicyclic ring
having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; a 3-8-membered saturated or partially
unsaturated ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or
partially unsaturated, or fully unsaturated bicyclic ring system
having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; wherein Ar.sup.1 is optionally substituted at
one or more carbon atoms with 0-5 occurrences of -Q-R.sup.5, and at
one or more substitutable nitrogen atoms with --R.sup.6 and each
occurrence of R.sup.6 is independently R', --COR',
--CO.sub.2(C.sub.1-6 aliphatic), --CON(R').sub.2,
--SO.sub.2N(R').sub.2, or --SO.sub.2R'; R.sup.3 and R.sup.4 are
each independently Z-R.sup.7, or R.sup.3 and R.sup.4 are taken
together to form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 3-8 membered ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur
wherein said ring is optionally substituted with 0-5 independent
occurrences of Y--R.sup.8; each occurrence of Q, Z, and Y is
independently a bond or an optionally substituted C.sub.1-C.sub.6
alkylidene chain wherein up to two non-adjacent methylene units of
Q are optionally replaced by CO, CO.sub.2, COCO, CONR, OCONR, NRNR,
NRNRCO, NRCO, NRCO.sub.2, NRCONR, SO, SO.sub.2, NRSO.sub.2,
SO.sub.2NR, NRSO.sub.2NR, O, S, or NR; each occurrence of R.sup.5,
R.sup.7 and R.sup.8 is independently R', halogen, NO.sub.2, CN,
OR', SR', N(R').sub.2, NR'C(O)R', NR'C(O)N(R').sub.2,
NR'CO.sub.2R', C(O)R', CO.sub.2R', OC(O)R', C(O)N(R').sub.2,
OC(O)N(R').sub.2, SOR', SO.sub.2R', SO.sub.2N(R').sub.2,
NR'SO.sub.2R', NR'SO.sub.2N(R').sub.2, PO(OR').sub.2, C(O)C(O)R',
or C(O)CH.sub.2C(O)R'; and each occurrence of R is independently
hydrogen or an optionally substituted C.sub.1-6 aliphatic group;
and each occurrence of R' is independently hydrogen or an
optionally substituted group selected from C.sub.1-8 aliphatic,
C.sub.6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a
heterocyclyl ring having 3-10 ring atoms, or wherein two
occurrences of R taken together, R and R' taken together, or two
occurrences of R' taken together, form an optionally substituted
saturated, partially unsaturated, or fully unsaturated 3-8 membered
ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; provided that: i) R.sup.3 and R.sup.4 are not
simultaneously hydrogen; and ii) when R.sup.3 and R.sup.4 are both
methyl, or R.sup.3 is methyl and R.sup.4 is (CH.sub.2).sub.2OH,
then Ar.sup.1 is not 3,4,5-trimethoxyphenyl.
2. The compound of claim 1, wherein Ar.sup.1 are optionally
substituted rings selected from: (a) a phenyl, indanyl, or naphthyl
ring; (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or (c) a
5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl ring
having 1-3 heteroatoms independently selected from oxygen,
nitrogen, or sulfur.
3. The compound of claim 1, wherein Ar.sup.1 are optionally
substituted rings selected from: (a) a phenyl ring; (b) a 5-6
membered heterocyclic ring having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; or (c) a 5-6 membered
monocyclic heteroaryl ring having 1-3 heteroatoms independently
selected from oxygen, nitrogen, or sulfur.
4. The compound of claim 1, wherein Ar.sup.1 is selected from any
one of a-bb: 133134135wherein x is 0-5.
5. The compound of claim 1, wherein Ar.sup.1 is optionally
substituted phenyl, pyrimidinyl, or pyridyl.
6. The compound of claim 1, wherein Ar.sup.1 is phenyl and is
substituted with two (x=2) or three (x=3) occurrrences of Q-R.sup.5
and Ar.sup.1 is one of the following structures: 136wherein each
occurrence of QR.sup.5 is independently CH.sub.2halogen, halogen,
CH.sub.2CN, CN, CH.sub.2CO.sub.2R', CO.sub.2R', CH.sub.2COR', COR',
R', CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR', OR', CH.sub.2SR', SR',
haloalkyl, CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2.
7. The compound of claim 1, wherein Q is independently a bond or is
an optionally substituted C.sub.1-C.sub.4 alkylidene chain wherein
up to two non-adjacent methylene units of Q are optionally replaced
by CO, CO.sub.2, CONR, OCONR, NRCO, NRCO.sub.2, NRSO.sub.2,
SO.sub.2NR, O, S, or NR; and each occurrence of R.sup.5 is
independently selected from R', halogen, NO.sub.2, CN, OR', SR',
N(R').sub.2, NR'C(O)R', NR'C(O)N(R').sub.2, NR'CO.sub.2R', C(O)R',
CO.sub.2R', OC(O)R', C(O)N(R').sub.2, OC(O)N(R').sub.2, SOR',
SO.sub.2R', SO.sub.2N(R').sub.2, NR'SO.sub.2R',
NR'SO.sub.2N(R').sub.2, PO(OR').sub.2, C(O)C(O)R', or
C(O)CH.sub.2C(O)R', and x is 0, 1, 2, or 3.
8. The compound of claim 1, wherein Q-R.sup.5 substituents on
Ar.sup.1 are CH.sub.2halogen, halogen, CH.sub.2CN, CN,
CH.sub.2CO.sub.2R', CO.sub.2R', CH.sub.2COR', COR', R',
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR', OR', CH.sub.2SR', SR',
haloalkyl, CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or two adjacent occurrences
of Q-R.sup.5, taken together with the atoms to which they are
bound, form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5-8-membered ring having 0-3
heteroatoms selected from nitrogen, oxygen, or sulfur.
9. The compound of claim 1, wherein Q-R.sup.5 substituents on
Ar.sup.1 are fluoro, iodo, chloro, bromo, COCH.sub.3,
CO.sub.2CH.sub.3, C.sub.1-4alkyl, NH.sub.2, CH.sub.2NH.sub.2, NHMe,
CH.sub.2NHMe, N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2,
CH.sub.2N(Et).sub.2, NH(phenyl), CO(C.sub.1-4alkyl),
CH.sub.2CO(C.sub.1-4alkyl), NHCO(C.sub.1-C.sub.4alkyl),
CH.sub.2NHCO(C.sub.1-4alkyl), CN, CH.sub.2CN, OH, C.sub.1-4alkoxy,
optionally substituted benzyloxy, optionally substituted phenyloxy,
CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe, optionally substituted
SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl), CONH.sub.2,
CH.sub.2PO(OR').sub.2, or an optionally substituted group selected
from a saturated, partially unsaturated, or fully unsaturated 5- or
6-membered ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
10. The compound of claim 1, wherein R.sup.1 and R.sup.2 groups of
formula I are each independently hydrogen, N(R').sub.2, SR, OR, or
TR, or R.sup.1 and R.sup.2, taken together form an optionally
substituted saturated, partially unsaturated, or fully unsaturated
5-membered ring having 0-2 heteroatoms independently selected from
N, O, or S.
11. The compound of claim 1, wherein R.sup.1 and R.sup.2 groups are
each independently hydrogen, OH, CH.sub.3, CH.sub.2CH.sub.3,
OCH.sub.3, CH.sub.2OH, CH.sub.2OCH.sub.3, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3, NH.sub.2, or CH.sub.2NH.sub.2, or R.sup.1 and
R.sup.2, taken together, form a fused optionally substituted
pyrrolyl, pyrazolyl, or imidazolyl ring.
12. The compound of claim 1, wherein R.sup.3 and R.sup.4 are each
independently Z-R.sup.7 wherein Z is an optionally substituted
C.sub.0-4 alkylidene chain wherein one methylene unit of Z is
optionally replaced by O, NR, NRCO, NRCO.sub.2, NRSO.sub.2, CONR,
C(O), C(O)O, and wherein R.sup.7 is selected from halogen, CN,
N(R').sub.2, NHCOR', or R', or wherein R.sup.3 and R.sup.4, taken
together form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
13. The compound of claim 1, wherein R.sup.3 and R.sup.4 are each
independently hydrogen, CN, halogen, OH, SH, NH.sub.2, CO.sub.2H,
COH, CONH.sub.2, SO.sub.2NH.sub.2, NO.sub.2,
(CH.sub.2).sub.nNRR.sup.7, wherein R and R.sup.7, taken together
with the nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur,
or R.sup.3 and R.sup.4, taken together with the atoms to which they
are bound, form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, and n is 0, 1, 2, 3, 4, or 5.
14. The compound of claim 1, wherein one of R.sup.3 or R.sup.4 is
hydrogen, and the other of R.sup.3 or R.sup.4 is
(CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is hydrogen,
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or
sulfur.
15. The compound of claim 14, wherein R.sup.3 is hydrogen.
16. The compound of claim 14, wherein R.sup.4 is hydrogen.
17. The compound of claim 1, wherein R.sup.3 and R.sup.4, taken
together with the atoms to which they are bound, form an optionally
substituted saturated, partially unsaturated, or fully unsaturated
5- or 6-membered ring having 0-3 heteroatoms independently selected
from nitrogen, oxygen, or sulfur, and wherein said ring is
optionally substituted with 0, 1, 2, 3, 4, or occurrences of
Y--R.sup.8.
18. The compound of claim 17, wherein each occurrence of Y--R.sup.8
is independently methyl, ethyl, t-butyl, fluoro, chloro, bromo,
oxo, CF.sub.3, OMe, OEt, CN, SO.sub.2Me, SO.sub.2NH.sub.2,
NH.sub.2, NHMe, N(Me).sub.2, SMe, SEt, OH, C(O)Me, NO.sub.2, or
CH.sub.2OH.
19. The compound of claim 1, having one of formulas I-A-i, I-A-ii,
I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, or I-E-i: 137138wherein q is
0-5.
20. The compound of claim 19, wherein Ar.sup.1 is: (a) a phenyl,
indanyl, or naphthyl ring; (b) a 5-6 membered heterocyclic ring
having 1-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; or (c) a 5-6 membered monocyclic or 9-10
membered bicyclic heteroaryl ring having 1-3 heteroatoms
independently selected from oxygen, nitrogen, or sulfur.
21. The compound of claim 19, wherein Ar.sup.1 is: (a) a phenyl
ring; (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or (c) a
5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms
independently selected from oxygen, nitrogen, or sulfur.
22. The compound of claim 19, wherein Ar.sup.1 is any one of a-bb:
139140141wherein Q and R.sup.5 are as defined generally above and
in subsets herein, and x is 0-5.
23. The compound of claim 19, wherein Ar.sup.1 is phenyl,
pyrimidinyl, or pyridyl.
24. The compound of claim 19, wherein Ar.sup.1 is phenyl and is
substituted with two (x=2) or three (x=3) occurrrences of Q-R.sup.5
and Ar.sup.1 is one of the following structures: 142wherein each
occurrence of QR.sup.5 is independently CH.sub.2halogen, halogen,
CH.sub.2CN, CN, CH.sub.2CO.sub.2R', CO.sub.2R', CH.sub.2COR', COR',
R', CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR', OR', CH.sub.2SR', SR',
haloalkyl, CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2.
25. The compound of claim 19, wherein Ar.sup.1 is optionally
substituted phenyl and compounds have one of formulas II-A-i,
II-A-ii, II-B-i, II-B-ii, II-C-i, II-C-ii, II-D-i, or II-E-i:
143144where x and q are each independently 0-5.
26. The compound of claim 25, wherein each occurrence of Q is
independently a bond or is an optionally substituted
C.sub.1-C.sub.4 alkylidene chain wherein up to two non-adjacent
methylene units of Q are optionally replaced by CO, CO.sub.2, CONR,
OCONR, NRCO, NRCO.sub.2, NRSO.sub.2, SO.sub.2NR, O, S, or NR; and
each occurrence of R.sup.5 is independently selected from R',
halogen, NO.sub.2, CN, OR', SR', N(R').sub.2, NR'C(O)R',
NR'C(O)N(R').sub.2, NR'CO.sub.2R', C(O)R', CO.sub.2R', OC(O)R',
C(O)N(R').sub.2, OC(O)N(R').sub.2, SOR', SO.sub.2R',
SO.sub.2N(R').sub.2, NR'SO.sub.2R', NR'SO.sub.2N(R').sub.2,
PO(OR').sub.2, C(O)C(O)R', or C(O)CH.sub.2C(O)R', and x is 0, 1, 2,
or 3.
27. The compound of claim 25, wherein each occurrence of Q-R.sup.5
is independently CH.sub.2halogen, halogen, CH.sub.2CN, CN,
CH.sub.2CO.sub.2R', CO.sub.2R', CH.sub.2COR', COR', R',
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR', OR', CH.sub.2SR', SR',
haloalkyl, CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or two adjacent occurrences
of Q-R.sup.5, taken together with the atoms to which they are
bound, form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5-8-membered ring having 0-3
heteroatoms selected from nitrogen, oxygen, or sulfur.
28. The compound of claim 25, wherein each occurrence of Q-R.sup.5
is independently fluoro, iodo, chloro, bromo, COCH.sub.3,
CO.sub.2CH.sub.3, C.sub.1-4alkyl, NH.sub.2, CH.sub.2NH.sub.2, NHMe,
CH.sub.2NHMe, N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2,
CH.sub.2N(Et).sub.2, NH(phenyl), CO(C.sub.1-4alkyl),
CH.sub.2CO(C.sub.1-4alkyl), NHCO(C.sub.1-4alkyl),
CH.sub.2NHCO(C.sub.1-4alkyl), CN, CH.sub.2CN, OH, C.sub.1-4alkoxy,
optionally substituted benzyloxy, optionally substituted phenyloxy,
CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe, optionally substituted
SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl), CONH.sub.2,
CH.sub.2PO(OR').sub.2, or an optionally substituted group selected
from a saturated, partially unsaturated, or fully unsaturated 5- or
6-membered ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
29. The compound of claim 25, wherein R.sup.1 and R.sup.2 are each
independently hydrogen, N(R').sub.2, SR, OR, or TR, or R.sup.1 and
R.sup.2, taken together form an optionally substituted saturated,
partially unsaturated, or fully unsaturated 5-membered ring having
0-2 heteroatoms independently selected from N, O, or S.
30. The compound of claim 29, wherein R.sup.1 and R.sup.2 are each
independently hydrogen, OH, CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3,
CH.sub.2OH, CH.sub.2OCH.sub.3, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3, NH.sub.2, or CH.sub.2NH.sub.2, or R.sup.1 and
R.sup.2, taken together, form a fused optionally substituted
pyrrolyl, pyrazolyl, or imidazolyl ring.
31. The compound of claim 25, wherein R.sup.3 is Z-R.sup.7, wherein
Z is a bond or is an optionally substituted C.sub.0-4 alkylidene
chain wherein one methylene unit of Z is optionally replaced by O,
NR, NRCO, NRCO.sub.2, NRSO.sub.2, CONR, C(O), C(O)O, and wherein
R.sup.7 is halogen, CN, N(R').sub.2, NHCOR', or R'.
32. The compound of claim 25, wherein R.sup.3 is
(CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1.
33. The compound of claim 25, wherein R.sup.4 is Z-R.sup.7, wherein
Z is a bond or is an optionally substituted C.sub.0-4 alkylidene
chain wherein one methylene unit of Z is optionally replaced by O,
NR, NRCO, NRCO.sub.2, NRSO.sub.2, CONR, C(O), C(O)O, and wherein
R.sup.7 is selected from halogen, CN, N(R').sub.2, NHCOR', or
R'.
34. The compound of claim 25, wherein R.sup.4 is (CH.sub.2),
halogen, (CH.sub.2).sub.nCN, (CH.sub.2).sub.nOR.sup.7,
(CH.sub.2).sub.nNRR.sup.7, (CH.sub.2).sub.nC(O)R.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7 (CH.sub.2).sub.nCH.sub.3,
(CH.sub.2).sub.nC(O)NRR.sup.7, (CH.sub.2).sub.nSR.sup.7, wherein
R.sup.7 is (CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an
optionally substituted 5- or 6-membered aryl, aralkyl, heteroaryl,
or heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1.
35. The compound of claim 25, wherein q is 0, 1, or 2, and each
occurrence of Y--R.sup.8 is independently methyl, ethyl, t-butyl,
fluoro, chloro, bromo, oxo, CF.sub.3, OMe, OEt, CN, SO.sub.2Me,
SO.sub.2NH.sub.2, NH.sub.2, NHMe, N(Me).sub.2, SMe, SEt, OH,
C(O)Me, NO.sub.2, or CH.sub.2OH.
36. The compound of claim 25, wherein compounds have one of
formulas II-A-i, II-B-i, or II-C-i, and the compound variables are
defined as: a) x is 0, 1, 2, or 3, and Q-R.sup.5 is
CH.sub.2halogen, halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R',
CO.sub.2R', CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2,
CH.sub.2OR', OR', CH.sub.2SR', SR', haloalkyl,
CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or Q-R.sup.5, taken together
with the atoms to which they are bound, form an optionally
substituted saturated, partially unsaturated, or fully unsaturated
5-8-membered ring having 0-3 heteroatoms selected from nitrogen,
oxygen, or sulfur; b) R.sup.1 and R.sup.2 are each independently
hydrogen, N(R').sub.2, SR, OR, or TR, or R.sup.1 and R.sup.2, taken
together form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5-membered ring having 0-2
heteroatoms independently selected from N, O, or S; and c) R.sup.3
is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1.
37. The compound of claim 25, wherein compounds have one of
formulas II-A-ii, I-B-ii, or II-C-ii, and one or more of the
compound variables are defined as: a) x is 0, 1, 2, or 3, and
Q-R.sup.5 is CH.sub.2halogen, halogen, CH.sub.2CN, CN,
CH.sub.2CO.sub.2R', CO.sub.2R', CH.sub.2COR', COR', R',
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR', OR', CH.sub.2SR', SR',
haloalkyl, CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or Q-R.sup.5, taken together
with the atoms to which they are bound, form an optionally
substituted saturated, partially unsaturated, or fully unsaturated
5-8-membered ring having 0-3 heteroatoms selected from nitrogen,
oxygen, or sulfur; b) R.sup.1 and R.sup.2 are each independently
hydrogen, N(R').sub.2, SR, OR, or TR, or R.sup.1 and R.sup.2, taken
together form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5-membered ring having 0-2
heteroatoms independently selected from N, O, or S; and c) R.sup.4
is (CH.sub.2), halogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1.
38. The compound of claim 25, wherein compounds have formula
II-E-i, and one or more of the compound variables are defined as:
a) x is 0, 1, 2, or 3, and Q-R.sup.5 is CH.sub.2halogen, halogen,
CH.sub.2CN, CN, CH.sub.2CO.sub.2R', CO.sub.2R', CH.sub.2COR', COR',
R', CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR', OR', CH.sub.2SR', SR',
haloalkyl, CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or Q-R.sup.5, taken together
with the atoms to which they are bound, form an optionally
substituted saturated, partially unsaturated, or fully unsaturated
5-8-membered ring having 0-3 heteroatoms selected from nitrogen,
oxygen, or sulfur; b) R.sup.1 and R.sup.2 are each independently
hydrogen, N(R').sub.2, SR, OR, or TR, or R.sup.1 and R.sup.2, taken
together form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5-membered ring having 0-2
heteroatoms independently selected from N, O, or S; and c) q is 0,
1, or 2, and each occurrence of Y--R.sup.8 is independently methyl,
ethyl, t-butyl, fluoro, chloro, bromo, oxo, CF.sub.3, OMe, OEt, CN,
SO.sub.2Me, SO.sub.2NH.sub.2, NH.sub.2, NHMe, N(Me).sub.2, SMe,
SEt, OH, C(O)Me, NO.sub.2, or CH.sub.2OH.
39. The compound of claim 1, selected from:
14514614714814915015115215315-
41551561571581591601611621631641651661671681691701711721731741751761771781-
79180181182183184185186187188189190191192193194195196197198199200201202203-
204205206207208209210211212213
40. A composition comprising a compound of claim 1, and a
pharmaceutically acceptable carrier, adjuvant, or vehicle.
41. The composition of claim 40, wherein the compound is in an
amount to detectably inhibit SYK, or ZAP-70 protein kinase
activity.
42. The composition of claim 40, additionally comprising a
therapeutic agent selected from an anti-inflammatory agent, an
anti-proliferative agent, an immunomodulatory or immunosuppressive
agent, or an agent for treating immunodeficiency disorders.
43. A method of inhibiting SYK or ZAP-70 kinase activity in: (a) a
patient; or (b) a biological sample; which method comprises
administering to said patient, or contacting said biological sample
with: a) a composition of claim 40; or b) a compound of claim
1.
44. A method of treating or lessening the severity of treatment or
lessening the severity of an immunodeficiency disorder,
inflammatory disease, allergic disease, autoimmune disease,
proliferative disorder, immunologically-mediated disease, or
respiratory disorder, comprising the step of administering to said
patient: a) a composition of claim 40; or b) a compound of claim
1.
45. The method according to claim 44, comprising the additional
step of administering to said patient an additional therapeutic
agent selected from an anti-inflammatory agent, an
anti-proliferative agent, an immunomodulatory or immunosuppressive
agent, or an agent for treating immunodeficiency disorders,
wherein: said additional therapeutic agent is appropriate for the
disease being treated; and said additional therapeutic agent is
administered together with said composition as a single dosage form
or separately from said composition as part of a multiple dosage
form.
46. The method according to claim 44, wherein the disease is an
immune disorder.
47. The method according to claim 44, wherein the disease is
asthma.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C.
.sctn.119 to U.S. Provisional Application No. 60/457,468, filed
Mar. 25, 2003, entitled "Thiazoles Useful as Inhibitors of Protein
Kinases", the entire contents of which is hereby incorporated by
reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful as
inhibitors of protein kinases. The invention also provides
pharmaceutically acceptable compositions comprising the compounds
of the invention and methods of using the compositions in the
treatment of various disorders.
BACKGROUND OF THE INVENTION
[0003] The search for new therapeutic agents has been greatly aided
in recent years by a better understanding of the structure of
enzymes and other biomolecules associated with diseases. One
important class of enzymes that has been the subject of extensive
study is protein kinases.
[0004] Protein kinases constitute a large family of structurally
related enzymes that are responsible for the control of a variety
of signal transduction processes within the cell. (See, Hardie, G.
and Hanks, S. The Protein Kinase Facts Book, I and II, Academic
Press, San Diego, Calif.: 1995). Protein kinases are thought to
have evolved from a common ancestral gene due to the conservation
of their structure and catalytic function. Almost all kinases
contain a similar 250-300 amino acid catalytic domain. The kinases
may be categorized into families by the substrates they
phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,
lipids, etc.). Sequence motifs have been identified that generally
correspond to each of these kinase families (See, for example,
Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et
al., Science 1991, 253, 407-414; Hiles et al., Cell 1992, 70,
419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al.,
EMBO J. 1994, 13, 2352-2361).
[0005] In general, protein kinases mediate intracellular signaling
by effecting a phosphoryl transfer from a nucleoside triphosphate
to a protein acceptor that is involved in a signaling pathway.
These phosphorylation events act as molecular on/off switches that
can modulate or regulate the target protein biological function.
These phosphorylation events are ultimately triggered in response
to a variety of extracellular and other stimuli. Examples of such
stimuli include environmental and chemical stress signals (e.g.,
osmotic shock, heat shock, ultraviolet radiation, bacterial
endotoxin, and H.sub.2O.sub.2), cytokines (e.g., interleukin-1
(IL-1) and tumor necrosis factor .alpha. (TNF-.alpha.)), and growth
factors (e.g., granulocyte macrophage-colony-stimulating factor
(GM-CSF), and fibroblast growth factor (FGF)). An extracellular
stimulus may affect one or more cellular responses related to cell
growth, migration, differentiation, secretion of hormones,
activation of transcription factors, muscle contraction, glucose
metabolism, control of protein synthesis, and regulation of the
cell cycle.
[0006] Many diseases are associated with abnormal cellular
responses triggered by protein kinase-mediated events as described
above. These diseases include, but are not limited to, autoimmune
diseases, inflammatory diseases, bone diseases, metabolic diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular
diseases, allergies and asthma, Alzheimer's disease, and
hormone-related diseases. Accordingly, there has been a substantial
effort in medicinal chemistry to find protein kinase inhibitors
that are effective as therapeutic agents.
[0007] Syk is a tyrosine kinase that plays a critical role in
Fc.epsilon.RI mediated mast cell degranulation and eosinophil
activation. Accordingly, Syk kinase is implicated in various
allergic disorders, in particular asthma. It has been shown that
Syk binds to the phosphorylated gamma chain of the Fc.epsilon.R1
receptor via N-terminal SH2 domains and is essential for downstream
signaling [Taylor et al., Mol. Cell. Biol. 1995, 15, 4149].
[0008] Inhibition of eosinophil apoptosis has been proposed as a
key mechanism for the development of blood and tissue eosinophilia
in asthma. IL-5 and GM-CSF are upregulated in asthma and are
proposed to cause blood and tissue eosinophilia by inhibition of
eosinophil apoptosis. Inhibition of eosinophil apoptosis has been
proposed as a key mechanism for the development of blood and tissue
eosinophilia in asthma. It has been reported that Syk kinase is
required for the prevention of eosinophil apoptosis by cytokines
(using antisense)[Yousefi et al., J. Exp. Med. 1996, 183,
1407].
[0009] The role of Syk in Fc.gamma.R dependent and independent
response in bone marrow derived macrophages has been determined by
using irradiated mouse chimeras reconstituted with fetal liver
cells from Syk -/- embryos. Syk deficient macrophages were
defective in phagocytosis induced by Fc.gamma.R but showed normal
phagocytosis in response to complement [Kiefer et al., Mol. Cell.
Biol. 1998, 18, 4209]. It has also been reported that aerosolized
Syk antisense suppresses Syk expression and mediator release from
macrophages [Stenton et al., J. Immunology 2000, 164, 3790].
[0010] ZAP-70 is essential for T-cell receptor signalling.
Expression of this tyrosine kinase is restricted to T-cells and
natural killer cells. The importance of ZAP-70 in T-cell function
has been demonstrated in human patients, human T-cell lines and
mice. Human patients suffering from a rare form of severe combined
deficiency syndrome (SCID) possess homozygous mutations in ZAP-70
(reviewed in Elder J. of Pedriatric Hematology/Oncology 1997,
19(6), 546-550). These patients have profound immunodeficiency,
lack CD8+ T-cells and have CD4+ T-cells that are unresponsive to
T-cell receptor (TCR)-mediated stimulation. Following TCR
activation these CD4+ cells show severe defects in Ca2+
mobilization, tyrosine phosphorylation of down-stream substrates,
proliferation and IL-2 production 70 (reviewed in Elder Pedriatric
Research 39, 743-748). Human Jurkat cells lacking ZAP-70 also
provide important insights into the critical role of ZAP-70 in
T-cell receptor signalling. A Jurkat clone (p116) with no
detectable ZAP-70 protein was shown to have defects in T-cell
receptor signalling which could be corrected by re-introduction of
wild type ZAP-70 (Williams et al., Molecular and Cellular Biology
1998, 18 (3), 1388-1399). Studies of mice lacking ZAP-70 also
demonstrate a requirement of ZAP-70 in T-cell receptor signalling.
ZAP-70-deficient mice have profound defects in T-cell development
and T-cell receptor signalling in thymocytes is impaired (Negishi
et al., Nature 1995 376, 435-438).
[0011] The importance of the kinase domain in ZAP-70 function is
demonstrated by studies of human patients and mice expressing
identical mutations in the DLAARN motif within the kinase domain of
ZAP-70. Inactivation of kinase activity by this mutation results in
defective T-cell receptor signalling (Elder et al., J. Immunology
2001, 656-661). Catalytically inactive ZAP-70 (Lys369Arg) was also
defective in restoring T-cell receptor signalling in a ZAP-70
deficient Jurkat cell clone (p116) (Williams et al., Molecular and
Cellular Biology 1998, 18 (3), 1388-1399).
[0012] Accordingly, there is a great need to develop compounds
useful as inhibitors of protein kinases. In particular, it would be
desirable to develop compounds that are useful as inhibitors of SYK
or ZAP-70, particularly given the inadequate treatments currently
available for the majority of the disorders implicated in their
activation.
SUMMARY OF THE INVENTION
[0013] It has now been found that compounds of this invention, and
pharmaceutically acceptable compositions thereof, are effective as
inhibitors of protein kinases. In certain embodiments, these
compounds are effective as inhibitors of SYK or ZAP-70 protein
kinases. These compounds have the general formula I: 1
[0014] or a pharmaceutically acceptable salt thereof, wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and Ar.sup.1 are as defined
below.
[0015] These compounds and pharmaceutically acceptable compositions
thereof are useful for treating or preventing a variety of
diseases, disorders or conditions, including, but not limited to,
immunodeficiency disorders, inflammatory diseases, allergic
diseases, autoimmune diseases, proliferative disorders,
immunologically-mediated diseases, or respiratory disorders, to
name a few. The compounds provided by this invention are also
useful for the study of kinases in biological and pathological
phenomena; the study of intracellular signal transduction pathways
mediated by such kinases; and the comparative evaluation of new
kinase inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0016] I General Description of Compounds of the Invention:
[0017] The present invention relates to a compound of formula I:
2
[0018] or a pharmaceutically acceptable salt thereof, wherein:
[0019] R.sup.1 and R.sup.2 are each independently R.sup.1, halogen,
CN, NO.sub.2, or TR, or R.sup.1 and R.sup.2 taken together form an
optionally substituted saturated, partially unsaturated, or fully
unsaturated 5- or 6-membered ring having 0-3 heteroatoms
independently selected from N, O, or S;
[0020] T is an optionally substituted C.sub.1-C.sub.4 alkylidene
chain wherein up to two methylene units of T are optionally and
independently replaced by O, N(R'), C(O), S, SO, or SO.sub.2;
[0021] Ar.sup.1 is an optionally substituted ring selected from: an
aryl group selected from a 5-6 membered monocyclic or an 8-10
membered bicyclic ring having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated
or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or an
8-10-membered saturated or partially unsaturated bicyclic ring
system having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; wherein Ar.sup.1 is optionally substituted at
one or more carbon atoms with 0-5 occurrences of -Q-R.sup.5, and at
one or more substitutable nitrogen atoms with --R.sup.6 and each
occurrence of R.sup.6 is independently R', --COR',
--CO.sub.2(C.sub.1-6 aliphatic), --CON(R').sub.2,
--SO.sub.2N(R').sub.2, or --SO.sub.2R';
[0022] R.sup.3 and R.sup.4 are each independently Z-R.sup.7, or
R.sup.3 and R.sup.4 are taken together to form an optionally
substituted saturated or partially unsaturated, or fully
unsaturated 3-8 membered ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur wherein said ring is
optionally substituted with 0-5 independent occurrences of
Y--R.sup.8;
[0023] each occurrence of Q, Z, and Y is independently a bond or an
optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up
to two non-adjacent methylene units of Q are optionally replaced by
CO, CO.sub.2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO.sub.2,
NRCONR, SO, SO.sub.2, NRSO.sub.2, SO.sub.2NR, NRSO.sub.2NR, O, S,
or NR;
[0024] each occurrence of R.sup.5, R.sup.7 and R.sup.8 is
independently R', halogen, NO.sub.2, CN, OR', SR', N(R').sub.2,
NR'C(O)R', NR'C(O)N(R').sub.2, NR'CO.sub.2R', C(O)R', CO.sub.2R',
OC(O)R', C(O)N(R').sub.2, OC(O)N(R').sub.2, SOR', SO.sub.2R',
SO.sub.2N(R').sub.2, NR'SO.sub.2R', NR'SO.sub.2N(R').sub.2,
PO(OR').sub.2, C(O)C(O)R', or C(O)CH.sub.2C(O)R'; and
[0025] each occurrence of R' is independently hydrogen or an
optionally substituted C.sub.1-6 aliphatic group; and each
occurrence of R' is independently hydrogen or an optionally
substituted group selected from C.sub.1-8 aliphatic, C.sub.6-10
aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl
ring having 3-10 ring atoms, or wherein two occurrences of R' taken
together, R and R' taken together, or two occurrences of R' taken
together, form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 3-8 membered ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur;
[0026] provided that:
[0027] i) R.sup.3 and R.sup.4 are not simultaneously hydrogen;
and
[0028] ii) when R.sup.3 and R.sup.4 are both methyl, or R.sup.3 is
methyl and R.sup.4 is (CH.sub.2).sub.2OH, then Ar.sup.1 is not
3,4,5-trimethoxyphenyl.
[0029] 2. Compounds and Definitions:
[0030] Compounds of this invention include those described
generally above, and are further illustrated by the classes,
subclasses, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated. For
purposes of this invention, the chemical elements are identified in
accordance with the Periodic Table of the Elements, CAS version,
Handbook of Chemistry and Physics, 75.sup.th Ed. Additionally,
general principles of organic chemistry are described in "Organic
Chemistry", Thomas Sorrell, University Science Books, Sausalito:
1999, and "March's Advanced Organic Chemistry", 5.sup.th Ed., Ed.:
Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,
the entire contents of which are hereby incorporated by
reference.
[0031] As described herein, compounds of the invention may
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention. It will be
appreciated that the phrase "optionally substituted" is used
interchangeably with the phrase "substituted or unsubstituted." In
general, the term "substituted", whether preceded by the term
"optionally" or not, refers to the replacement of hydrogen radicals
in a given structure with the radical of a specified substituent.
Unless otherwise indicated, an optionally substituted group may
have a substituent at each substitutable position of the group, and
when more than one position in any given structure may be
substituted with more than one substituent selected from a
specified group, the substituent may be either the same or
different at every position. Combinations of substituents
envisioned by this invention are preferably those that result in
the formation of stable or chemically feasible compounds. The term
"stable", as used herein, refers to compounds that are not
substantially altered when subjected to conditions to allow for
their production, detection, and preferably their recovery,
purification, and use for one or more of the purposes disclosed
herein. In some embodiments, a stable compound or chemically
feasible compound is one that is not substantially altered when
kept at a temperature of 40.degree. C. or less, in the absence of
moisture or other chemically reactive conditions, for at least a
week.
[0032] The term "aliphatic" or "aliphatic group", as used herein,
means a straight-chain (i.e., unbranched) or branched, substituted
or unsubstituted hydrocarbon chain that is completely saturated or
that contains one or more units of unsaturation, or a monocyclic
hydrocarbon or bicyclic hydrocarbon that is completely saturated or
that contains one or more units of unsaturation, but which is not
aromatic (also referred to herein as "carbocycle" "cycloaliphatic"
or "cycloalkyl"), that has a single point of attachment to the rest
of the molecule. Unless otherwise specified, aliphatic groups
contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic
groups contain 1-10 aliphatic carbon atoms. In other embodiments,
aliphatic groups contain 1-8 aliphatic carbon atoms. In still other
embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms,
and in yet other embodiments aliphatic groups contain 1-4 aliphatic
carbon atoms. In some embodiments, "cycloaliphatic" (or
"carbocycle" or "cycloalkyl") refers to a monocyclic
C.sub.3-C.sub.8 hydrocarbon or bicyclic C.sub.8-C.sub.12
hydrocarbon that is completely saturated or that contains one or
more units of unsaturation, but which is not aromatic, that has a
single point of attachment to the rest of the molecule wherein any
individual ring in said bicyclic ring system has 3-7 members.
Suitable aliphatic groups include, but are not limited to, linear
or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl
groups and hybrids thereof such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0033] The term "heteroaliphatic", as used herein, means aliphatic
groups wherein one or two carbon atoms are independently replaced
by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.
Heteroaliphatic groups may be substituted or unsubstituted,
branched or unbranched, cyclic or acyclic, and include
"heterocycle", "heterocyclyl", "heterocycloaliphatic", or
"heterocyclic" groups.
[0034] The term "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" as used herein means
non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in
which one or more ring members is an independently selected
heteroatom. In some embodiments, the "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" group has three to
fourteen ring members in which one or more ring members is a
heteroatom independently selected from oxygen, sulfur, nitrogen, or
phosphorus, and each ring in the system contains 3 to 7 ring
members.
[0035] The term "heteroatom" means one or more of oxygen, sulfur,
nitrogen, phosphorus, or silicon (including, any oxidized form of
nitrogen, sulfur, phosphorus, or silicon; the quaternized form of
any basic nitrogen or; a substitutable nitrogen of a heterocyclic
ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl) or NR.sup.+ (as in N-substituted pyrrolidinyl)).
[0036] The term "unsaturated", as used herein, means that a moiety
has one or more units of unsaturation.
[0037] The term "alkoxy", or "thioalkyl", as used herein, refers to
an alkyl group, as previously defined, attached to the principal
carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl")
atom.
[0038] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means
alkyl, alkenyl or alkoxy, as the case may be, substituted with one
or more halogen atoms. The term "halogen" means F, Cl, Br, or
I.
[0039] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic,
bicyclic, and tricyclic ring systems having a total of five to
fourteen ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3 to 7 ring
members. The term "aryl" may be used interchangeably with the term
"aryl ring". The term "aryl" also refers to heteroaryl ring systems
as defined hereinbelow.
[0040] The term "heteroaryl", used alone or as part of a larger
moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to
monocyclic, bicyclic, and tricyclic ring systems having a total of
five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or
more heteroatoms, and wherein each ring in the system contains 3 to
7 ring members. The term "heteroaryl" may be used interchangeably
with the term "heteroaryl ring" or the term "heteroaromatic".
[0041] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the
like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy
and the like) group may contain one or more substituents. Suitable
substituents on the unsaturated carbon atom of an aryl or
heteroaryl group are selected from halogen; --R.degree.;
--OR.degree.; --SR.degree.; 1,2-methylene-dioxy; 1,2-ethylenedioxy;
phenyl (Ph) optionally substituted with R.degree.; --O(Ph)
optionally substituted with R.degree.; --(CH.sub.2).sub.1-2(Ph),
optionally substituted with R.degree.; --CH.dbd.CH(Ph), optionally
substituted with R.degree.; --NO.sub.2; --CN; --N(R.degree.).sub.2;
--NR.degree.C(O)R.degree.; --NR.degree.C(O)N(R.degree.).sub.2;
--NR.degree.CO.sub.2R.degree.; --NR.degree.NR.degree.C(O)R.degree.;
--NR.degree.NR.degree.C(O)N(R.degree.).sub.2;
--NR.degree.NR.degree.CO.su- b.2R.degree.; --C(O)C(O)R.degree.;
--C(O)CH.sub.2C(O)R.degree.; --CO.sub.2R.degree.; --C(O)R.degree.;
--C(O)N(R.degree.).sub.2; --OC(O)N(R.degree.).sub.2;
--S(O).sub.2R.degree.; --SO.sub.2N(R.degree.).- sub.2;
--S(O)R.degree.; --NR.degree.SO.sub.2N(R.degree.).sub.2;
--NR.degree.SO.sub.2R.degree.; --C(.dbd.S)N(R.degree.).sub.2;
--C(.dbd.NH)--N(R.degree.).sub.2; or
--(CH.sub.2).sub.0-2NHC(O)R.degree. wherein each independent
occurrence of R.degree. is selected from hydrogen, optionally
substituted C.sub.1-6 aliphatic, an unsubstituted 5-6 membered
heteroaryl or heterocyclic ring, phenyl, --O(Ph), or
--CH.sub.2(Ph), or, notwithstanding the definition above, two
independent occurrences of R.degree., on the same substituent or
different substituents, taken together with the atom(s) to which
each R.degree. group is bound, form a 3-8-membered cycloalkyl,
heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. Optional
substituents on the aliphatic group of R.degree. are selected from
NH.sub.2, NH(C.sub.1-4aliphatic), N(C.sub.1-4aliphatic).sub.2,
halogen, C.sub.1-4aliphatic, OH, O(C.sub.1-4aliphatic), NO.sub.2,
CN, CO.sub.2H, CO.sub.2(C.sub.1-4aliphat- ic), O(haloC.sub.1-4
aliphatic), or haloC.sub.1-4aliphatic, wherein each of the
foregoing C.sub.1-4aliphatic groups of R.degree. is
unsubstituted.
[0042] An aliphatic or heteroaliphatic group, or a non-aromatic
heterocyclic ring may contain one or more substituents. Suitable
substituents on the saturated carbon of an aliphatic or
heteroaliphatic group, or of a non-aromatic heterocyclic ring are
selected from those listed above for the unsaturated carbon of an
aryl or heteroaryl group and additionally include the following:
.dbd.O, .dbd.S, .dbd.NNHR, .dbd.NN(R*).sub.2, .dbd.NNHC(O)R*,
.dbd.NNHCO.sub.2(alkyl), =NNHSO.sub.2(alkyl), or .dbd.NR*, where
each R* is independently selected from hydrogen or an optionally
substituted C.sub.1-6 aliphatic. Optional substituents on the
aliphatic group of R* are selected from NH.sub.2, NH(C.sub.1-4
aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4
aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H,
CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or
halo(C.sub.1-4 aliphatic), wherein each of the foregoing
C.sub.1-4aliphatic groups of R* is unsubstituted.
[0043] Optional substituents on the nitrogen of a non-aromatic
heterocyclic ring are selected from --R.sup.+, --N(R.sup.+).sub.2,
--C(O)R.sup.+, --CO.sub.2R.sup.+, --C(O)C(O)R.sup.+,
--C(O)CH.sub.2C(O)R.sup.+, --SO.sub.2R.sup.+,
--SO.sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2,
--C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+SO.sub.2R.sup.+;
wherein R.sup.+ is hydrogen, an optionally substituted C.sub.1-6
aliphatic, optionally substituted phenyl, optionally substituted
--O(Ph), optionally substituted --CH.sub.2(Ph), optionally
substituted --(CH.sub.2).sub.1-2(Ph); optionally substituted
--CH.dbd.CH(Ph); or an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring having one to four heteroatoms independently
selected from oxygen, nitrogen, or sulfur, or, notwithstanding the
definition above, two independent occurrences of R.sup.+, on the
same substituent or different substituents, taken together with the
atom(s) to which each R.sup.+ group is bound, form a 3-8-membered
cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Optional substituents on the aliphatic group or the phenyl
ring of R.sup.+ are selected from NH.sub.2, NH(C.sub.1-4
aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4
aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H,
CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or
halo(C.sub.1-4 aliphatic), wherein each of the foregoing
C.sub.1-4aliphatic groups of R.sup.+ is unsubstituted.
[0044] The term "alkylidene chain" refers to a straight or branched
carbon chain that may be fully saturated or have one or more units
of unsaturation and has two points of attachment to the rest of the
molecule.
[0045] As detailed above, in some embodiments, two independent
occurrences of R.degree. (or R.sup.+, or any other variable
similarly defined herein), are taken together together with the
atom(s) to which each variable is bound to form a 3-8-membered
cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Exemplary rings that are formed when two independent
occurrences of R.degree. (or R.sup.+, or any other variable
similarly defined herein) are taken together with the atom(s) to
which each variable is bound include, but are not limited to the
following: a) two independent occurrences of R.degree. (or R.sup.+,
or any other variable similarly defined herein) that are bound to
the same atom and are taken together with that atom to form a ring,
for example, N(R.degree.).sub.2, where both occurrences of
R.degree. are taken together with the nitrogen atom to form a
piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two
independent occurrences of R.degree. (or R.sup.+, or any other
variable similarly defined herein) that are bound to different
atoms and are taken together with both of those atoms to form a
ring, for example where a phenyl group is substituted with two
occurrences of OR.degree. 3
[0046] these two occurrences of R.degree. are taken together with
the oxygen atoms to which they are bound to form a fused 6-membered
oxygen containing ring: 4
[0047] It will be appreciated that a variety of other rings can be
formed when two independent occurrences of R.degree. (or R.sup.+,
or any other variable similarly defined herein) are taken together
with the atom(s) to which each variable is bound and that the
examples detailed above are not intended to be limiting.
[0048] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention. Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools or probes in biological assays.
[0049] 3. Description of Exemplary Compounds:
[0050] As described generally above for compounds of general
formula I, Ar.sup.1 is an optionally substituted ring selected
from: an aryl group selected from a 5-6 membered monocyclic or an
8-10 membered bicyclic ring having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated
or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or an
8-10-membered saturated or partially unsaturated bicyclic ring
system having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, wherein Ar.sup.1 is optionally substituted at
one or more carbon atoms with 0-5 occurrences of -Z-R.sup.5, and at
one or more substitutable nitrogen atoms with --R.sup.6.
[0051] Preferred Ar.sup.1 groups of formula I are optionally
substituted rings selected from:
[0052] (a) a phenyl, indanyl, or naphthyl ring;
[0053] (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or
[0054] (c) a 5-6 membered monocyclic or 9-10 membered bicyclic
heteroaryl ring having 1-3 heteroatoms independently selected from
oxygen, nitrogen, or sulfur.
[0055] More preferred Ar.sup.1 groups of formula I are optionally
substituted rings selected from:
[0056] (a) a phenyl ring;
[0057] (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or
[0058] (c) a 5-6 membered monocyclic heteroaryl ring having 1-3
heteroatoms independently selected from oxygen, nitrogen, or
sulfur.
[0059] In still other embodiments, Ar.sup.1 groups of formula I are
optionally substituted rings selected from any one of a-bb: 567
[0060] wherein x is 0-5.
[0061] Most preferred Ar.sup.1 rings are phenyl, pyrimidinyl, or
pyridyl.
[0062] In still other embodiments, for compounds described
generally above and in classes and subclasses herein, Ar.sup.1 is
not 3,4,5-trimethoxyphenyl.
[0063] As described generally above for compounds of general
formula I, Ar.sup.1 is optionally substituted with up to 5
independent occurrences of Q-R.sup.5, wherein each occurrence of Q
is independently a bond or is an optionally substituted
C.sub.1-C.sub.6 alkylidene chain wherein up to two non-adjacent
methylene units of Q are optionally replaced by CO, CO.sub.2, COCO,
CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO.sub.2, NRCONR, SO, SO.sub.2,
NRSO.sub.2, SO.sub.2NR, NRSO.sub.2NR, O, S, or NR; and each
occurrence of R.sup.5 is independently R', halogen, NO.sub.2, CN,
OR', SR', N(R').sub.2, NR'C(O)R', NR'C(O)N(R').sub.2,
NR'CO.sub.2R', C(O)R', CO.sub.2R', OC(O)R', C(O)N(R').sub.2,
OC(O)N(R').sub.2, SOR', SO.sub.2R', SO.sub.2N(R').sub.2,
NR'SO.sub.2R', NR'SO.sub.2N(R').sub.2, PO(OR').sub.2, C(O)C(O)R',
or C(O)CH.sub.2C(O)R'. In preferred embodiments, x is 0, 1, 2, or
3. In other preferred embodiments, x is 1, 2, or 3.
[0064] In yet other preferred embodients, Q is independently a bond
or is an optionally substituted C.sub.1-C.sub.4 alkylidene chain
wherein up to two non-adjacent methylene units of Q are optionally
replaced by CO, CO.sub.2, CONR, OCONR, NRCO, NRCO.sub.2,
NRSO.sub.2, SO.sub.2NR, O, S, or NR; and each occurrence of R.sup.5
is independently selected from R', halogen, NO.sub.2, CN, OR', SR',
N(R').sub.2, NR'C(O)R', NR'C(O)N(R').sub.2, NR'CO.sub.2R', C(O)R',
CO.sub.2R', OC(O)R', C(O)N(R').sub.2, OC(O)N(R').sub.2, SOR',
SO.sub.2R', SO.sub.2N(R').sub.2, NR'SO.sub.2R',
NR'SO.sub.2N(R').sub.2, PO(OR').sub.2, C(O)C(O)R', or
C(O)CH.sub.2C(O)R', and x is 0, 1, 2, or 3. In preferred
embodiments, x is 1, 2, or 3.
[0065] Preferred Q-R.sup.5 substituents on Ar.sup.1 are
CH.sub.2halogen, halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R',
CO.sub.2R', CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2,
CH.sub.2OR', OR', CH.sub.2SR', SR', haloalkyl,
CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or two adjacent occurrences
of Q-R.sup.5, taken together with the atoms to which they are
bound, form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5-8-membered ring having 0-3
heteroatoms selected from nitrogen, oxygen, or sulfur.
[0066] More preferred Q-R.sup.5 substituents on Ar.sup.1 are
fluoro, iodo, chloro, bromo, COCH.sub.3, CO.sub.2CH.sub.3,
C.sub.1-4alkyl (for example, methyl, ethyl, propyl, cyclopropyl,
n-butyl, cyclobuyl, or t-butyl), NH.sub.2, CH.sub.2NH.sub.2, NHMe,
CH.sub.2NHMe, N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2,
CH.sub.2N(Et).sub.2, NH(phenyl), CO(C.sub.1-4alkyl),
CH.sub.2CO(C.sub.1-4alkyl), NHCO(C.sub.1-4alkyl),
CH.sub.2NHCO(C.sub.1-4alkyl), CN, CH.sub.2CN, OH, C.sub.1-4alkoxy
(for example, OCH.sub.3, OCH.sub.2CH.sub.3,
O(CH.sub.2).sub.2CH.sub.3, or O(CH.sub.2).sub.3CH.sub.3),
optionally substituted benzyloxy, optionally substituted phenyloxy,
CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe, optionally substituted
SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl), CONH.sub.2,
CH.sub.2PO(OR').sub.2, or an optionally substituted group selected
from a saturated, partially unsaturated, or fully unsaturated 5- or
6-membered ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. Other preferred Ar.sup.1 substituents
are those substituents where two adjacent occurrences of Q-R.sup.5,
taken together with the atoms to which they are bound, and include
a fused optionally substituted saturated, partially unsaturated, or
fully unsaturated 5- or 6-membered ring having 0-3 heteroatoms
selected from nitrogen, oxygen, or sulfur. In more preferred
embodiments, these fused substituents formed by two adjacent
occurrences of Q-R.sup.5 include an optionally substituted group
selected from methylenedioxy, ethylenedioxy, propylenedioxy,
thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, phenyl,
pyridyl, pyrimidinyl, furyl, thiophene, pyran, pyrrolidinyl,
piperidinyl, piperazinyl, or morpholinyl.
[0067] In yet other embodiments, Ar.sup.1 is phenyl and is
substituted with two occurrences (x=2) of Q-R.sup.5 and Ar.sup.1
is: 8
[0068] wherein each occurrence of QR.sup.5 is independently
CH.sub.2halogen, halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R',
CO.sub.2R', CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2,
CH.sub.2OR', OR', CH.sub.2SR', SR', haloalkyl,
CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2. In certain preferred
embodiments, each occurrence of QR.sup.5 is independently fluoro,
iodo, chloro, bromo, COCH.sub.3, CO.sub.2CH.sub.3, C.sub.1-4alkyl
(for example, methyl, ethyl, propyl, cyclopropyl, n-butyl,
cyclobuyl, or t-butyl), NH.sub.2, CH.sub.2NH.sub.2, NHMe,
CH.sub.2NHMe, N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2,
CH.sub.2N(Et).sub.2, NH(phenyl), CO(C.sub.1-4alkyl),
CH.sub.2CO(C.sub.1-4alkyl), NHCO(C.sub.1-4alkyl),
CH.sub.2NHCO(C.sub.1-4alkyl), CN, CH.sub.2CN, OH, C.sub.1-4alkoxy
(for example, OCH.sub.3, OCH.sub.2CH.sub.3,
O(CH.sub.2).sub.2CH.sub.3, or O(CH.sub.2).sub.3CH.sub.3),
optionally substituted benzyloxy, optionally substituted phenyloxy,
CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe, optionally substituted
SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl), CONH.sub.2,
CH.sub.2PO(OR').sub.2, or an optionally substituted group selected
from a saturated, partially unsaturated, or fully unsaturated 5- or
6-membered ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. In still other preferred embodiments,
both occurrences of QR.sup.5 are methyl. In yet other preferred
embodiments, at least one occurrence of QR.sup.5 is CF.sub.3.
[0069] In yet other embodiments, Ar.sup.1 is phenyl and is
substituted with three occurrences (x=3) of Q-R.sup.5 and Ar.sup.1
is: 9
[0070] wherein each occurrence of QR.sup.5 is independently
CH.sub.2halogen, halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R',
CO.sub.2R', CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2,
CH.sub.2OR', OR', CH.sub.2SR', SR', haloalkyl,
CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2. In certain preferred
embodiments, each occurrence of QR.sup.5 is independently fluoro,
iodo, chloro, bromo, COCH.sub.3, CO.sub.2CH.sub.3, C.sub.1-4alkyl
(for example, methyl, ethyl, propyl, cyclopropyl, n-butyl,
cyclobuyl, or t-butyl), NH.sub.2, CH.sub.2NH.sub.2, NHMe,
CH.sub.2NHMe, N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2,
CH.sub.2N(Et).sub.2, NH(phenyl), CO(C.sub.1-4alkyl),
CH.sub.2CO(C.sub.1-4alkyl), NHCO(C.sub.1-4alkyl),
CH.sub.2NHCO(C.sub.1-4alkyl), CN, CH.sub.2CN, OH, C.sub.1-4alkoxy
(for example, OCH.sub.3, OCH.sub.2CH.sub.3,
O(CH.sub.2).sub.2CH.sub.3, or O(CH.sub.2).sub.3CH.sub.3),
optionally substituted benzyloxy, optionally substituted phenyloxy,
CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe, optionally substituted
SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl), CONH.sub.2,
CH.sub.2PO(OR').sub.2, or an optionally substituted group selected
from a saturated, partially unsaturated, or fully unsaturated 5- or
6-membered ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. In still other preferred embodiments,
each occurrence of QR.sup.5 is independently fluoro, iodo, chloro,
bromo, COCH.sub.3, CO.sub.2CH.sub.3, C.sub.1-4alkyl (for example,
methyl, ethyl, propyl, cyclopropyl, n-butyl, cyclobuyl, or
t-butyl), NH.sub.2, CH.sub.2NH.sub.2, NHMe, CH.sub.2NHMe,
N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2, CH.sub.2N(Et).sub.2,
NH(phenyl), CO(C.sub.1-4alkyl), CH.sub.2CO(C.sub.1-4alkyl),
NHCO(C.sub.1-4alkyl), CH.sub.2NHCO(C.sub.1-4a- lkyl), CN,
CH.sub.2CN, OH, optionally substituted benzyloxy, optionally
substituted phenyloxy, CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe,
optionally substituted SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl),
CONH.sub.2, CH.sub.2PO(OR').sub.2, or an optionally substituted
group selected from a saturated, partially unsaturated, or fully
unsaturated 5- or 6-membered ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0071] Each of the Q-R.sup.5 substituents described above are also
optionally further substituted with one or more groups
independently selected from R, OR, N(R').sub.2, SO.sub.2R, halogen,
NO.sub.2, CN, SR, SO.sub.2N(R).sub.2, CO.sub.2R, C(O)R, or oxo. In
more preferred embodiments, each of the Q-R.sup.5 groups described
above are also optionally further substituted with one or two
groups independently selected from methyl, ethyl, t-butyl, fluoro,
chloro, bromo, oxo, CF.sub.3, OMe, OEt, CN, SO.sub.2Me,
SO.sub.2NH.sub.2, NH.sub.2, NHMe, N(Me).sub.2, SMe, SEt, OH,
C(O)Me, NO.sub.2, or CH.sub.2OH.
[0072] As described generally above for compounds of general
formula I, R.sup.1 and R.sup.2 are each independently R, halogen,
CN, NO.sub.2, or TR, or R.sup.1 and R.sup.2 taken together form an
optionally substituted saturated, partially unsaturated, or fully
unsaturated 5- or 6-membered ring having 0-3 heteroatoms
independently selected from N, O, or S. Preferred R.sup.1 and
R.sup.2 groups of formula I are hydrogen, N(R).sub.2, SR, OR, or
TR, or R.sup.1 and R.sup.2, taken together form an optionally
substituted saturated, partially unsaturated, or fully unsaturated
5-membered ring having 0-2 heteroatoms independently selected from
N, O, or S. More preferred R.sup.1 and R.sup.2 groups are hydrogen,
OH, CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2OCH.sub.3, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3, NH.sub.2,
or CH.sub.2NH.sub.2, or R.sup.1 and R.sup.2, taken together, form a
fused optionally substituted pyrrolyl, pyrazolyl, or imidazolyl
ring. Still other preferred groups include hydrogen, NH.sub.2, or
CH.sub.2NH.sub.2.
[0073] As described generally above for compounds of formula I,
R.sup.3 and R.sup.4 are each independently Z-R.sup.7, wherein Z is
an optionally substituted C.sub.1-6alkylidene chain wherein up to
three non-adjacent methylene units are optionally replaced by CO,
CO.sub.2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO.sub.2,
NRCONR, SO, SO.sub.2, NRSO.sub.2, SO.sub.2NR, NRSO.sub.2NR, O, S,
or NR, and each occurrence of R.sup.7 is independently R', halogen,
NO.sub.2, CN, OR', SR', N(R').sub.2, NR'C(O)R', NR'C(O)N(R').sub.2,
NR'CO.sub.2R', C(O)R', CO.sub.2R', OC(O)R', C(O)N(R').sub.2,
OC(O)N(R').sub.2, SOR', SO.sub.2R', SO.sub.2N(R').sub.2,
NR'SO.sub.2R', NR'SO.sub.2N(R').sub.2, PO(OR').sub.2, C(O)C(O)R',
or C(O)CH.sub.2C(O)R', or R.sup.3 and R.sup.4 are taken together to
form an optionally substituted saturated, partially unsaturated, or
fully unsaturated 3-8 membered ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0074] In preferred embodiments R.sup.3 and R.sup.4 are each
independently Z-R.sup.7 wherein Z is an optionally substituted
C.sub.0-4 alkylidene chain wherein one methylene unit of Z is
optionally replaced by O, NR, NRCO, NRCO.sub.2, NRSO.sub.2, CONR,
C(O), C(O)O, and wherein R.sup.7 is selected from halogen, CN,
N(R').sub.2, NHCOR', or R', or wherein R.sup.3 and R.sup.4, taken
together form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0075] In other preferred embodiments, R.sup.3 and R.sup.4 are each
independently hydrogen, CN, halogen, OH, SH, NH.sub.2, CO.sub.2H,
COH, CONH.sub.2, SO.sub.2NH.sub.2, NO.sub.2,
(CH.sub.2).sub.nNRR.sup.7, wherein R and R.sup.7, taken together
with the nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur,
or R.sup.3 and R.sup.4, taken together with the atoms to which they
are bound, form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, and n is 0, 1, 2, 3, 4, or 5.
[0076] In still other preferred embodiments, one of R.sup.3 or
R.sup.4 is hydrogen, and the other of R.sup.3 or R.sup.4 is
(CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is hydrogen,
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur.
In some embodiments, for compounds described directly above,
R.sup.3 is hydrogen. In other embodiments, for compounds described
directly above, R.sup.4 is hydrogen.
[0077] In yet other preferred embodiments, R.sup.3 or R.sup.4 are
each independently hydrogen, (CH.sub.2).sub.nOR.sup.7,
(CH.sub.2).sub.nNRR.sup- .7, (CH.sub.2).sub.nCH.sub.3,
(CH.sub.2).sub.nSR.sup.7, (CH.sub.2).sub.nC(O)R.sup.7, or
(CH.sub.2).sub.nC(O)R.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur,
wherein n is 0 or 1 and m is 0 or 1, or R.sup.3 and R.sup.4, taken
together with the atoms to which they are bound, form an optionally
substituted saturated, partially unsaturated, or fully unsaturated
5- or 6-membered ring having 0-3 heteroatoms independently selected
from nitrogen, oxygen, or sulfur. In some preferred embodiments,
R.sup.3 is hydrogen, and R.sup.4 is (CH.sub.2).sub.nOR.sup.7,
(CH.sub.2).sub.nNRR.sup.7, (CH.sub.2).sub.nCH.sub.3,
(CH.sub.2).sub.nSR.sup.7 (CH.sub.2).sub.nC(O)R.sup.7, or
(CH.sub.2).sub.nC(O)R.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1 and m is 0 or 1. In other preferred embodiments, R.sup.4
is hydrogen and R.sup.3 is (CH.sub.2).sub.nOR.sup.7,
(CH.sub.2).sub.nNRR.sup.7, (CH.sub.2).sub.nCH.sub.3,
(CH.sub.2).sub.nSR.sup.7, (CH.sub.2).sub.nC(O)R.sup.7, or
(CH.sub.2).sub.nC(O)R.sup.7, R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur,
wherein n is 0 or 1 and m is 0 or 1. In still other preferred
embodiments, R.sup.3 and R.sup.4, taken together with the atoms to
which they are bound, form an optionally substituted saturated,
partially unsaturated, or fully unsaturated 5- or 6-membered ring
having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, and wherein said ring is optionally substituted
with 0, 1, 2, 3, 4, or 5 occurrences of Y--R.sup.8. In preferred
embodiments, each occurrence of Y--R.sup.8 is independently methyl,
ethyl, t-butyl, fluoro, chloro, bromo, oxo, CF.sub.3, OMe, OEt, CN,
SO.sub.2Me, SO.sub.2NH.sub.2, NH.sub.2, NHMe, N(Me).sub.2, SMe,
SEt, OH, C(O)Me, NO.sub.2, or CH.sub.2OH.
[0078] The present invention additionally provides compounds
wherein at least one of R.sup.3 or R.sup.4 is methyl and compounds
have one of formulas I-A-i or I-A-ii: 10
[0079] In other preferred embodiments at least one of R.sup.3 or
R.sup.4 is (CH.sub.2).sub.nNRR.sup.7 and compounds have one of
formulas I-B-i or I-B-ii: 11
[0080] In other preferred embodiments at least one of R.sup.3 or
R.sup.4 is (CH.sub.2).sub.nOR.sup.7 and compounds have one of
formulas I-C-i or I-C-ii: 12
[0081] In yet other preferred embodiments both R.sup.3 and R.sup.4
are methyl and compounds have formula I-D-i, or R.sup.3 and
R.sup.4, taken together, form an optionally substituted phenyl ring
and compounds have formula I-E-i: 13
[0082] wherein q is 0-5.
[0083] In general, for compounds of formulas I-A-i, I-A-ii, I-B-i,
I-B-ii, I-C-i, I-C-ii, I-D-i, and I-E-i, Ar.sup.1 is an optionally
substituted ring selected from: an aryl group selected from a 5-6
membered monocyclic or an 8-10 membered bicyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; a 3-8-membered saturated or partially unsaturated
monocyclic ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or
partially unsaturated bicyclic ring system having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, wherein
Ar.sup.1 is optionally substituted at one or more carbon atoms with
0-5 occurrences of -Z-R.sup.5, and at one or more substitutable
nitrogen atoms with --R.sup.6.
[0084] Preferred Ar.sup.1 groups for compounds of formulas I-A-i,
I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, and I-E-i are
optionally substituted rings selected from:
[0085] (a) a phenyl, indanyl, or naphthyl ring;
[0086] (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or
[0087] (c) a 5-6 membered monocyclic or 9-10 membered bicyclic
heteroaryl ring having 1-3 heteroatoms independently selected from
oxygen, nitrogen, or sulfur.
[0088] More preferred Ar.sup.1 groups for compounds of formulas
I-A-i, I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, and I-E-i are
optionally substituted rings selected from:
[0089] (a) a phenyl ring;
[0090] (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or
[0091] (c) a 5-6 membered monocyclic heteroaryl ring having 1-3
heteroatoms independently selected from oxygen, nitrogen, or
sulfur.
[0092] In still other embodiments, preferred Ar.sup.1 groups for
compounds of formulas I-A-i, I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii,
I-D-i, and I-E-i are optionally substituted rings selected from any
one of a-bb: 141516
[0093] wherein Q and R.sup.5 are as defined generally above and in
subsets herein, and x is 0-5.
[0094] Preferred Ar.sup.1 rings for compounds of formulas I-A-i,
I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, and I-E-i are phenyl,
pyrimidinyl, or pyridyl.
[0095] In still other embodiments, for compounds of formulas I-A-i,
I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, and I-E-i, Ar.sup.1 is
not 3,4,5-trimethoxyphenyl.
[0096] In preferred embodiments, for compounds of formulas I-A-i,
I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, and I-E-i, Ar.sup.1 is
optionally substituted phenyl and compounds have one of formulas
II-A-i, II-A-ii, II-B-i, II-B-ii, II-C-i, II-C-ii, II-D-i, and
II-E-i: 1718
[0097] where x and q are each independently 0-5.
[0098] As described generally above, Ar.sup.1 is optionally
substituted with up to 5 independent occurrences of Q-R.sup.5,
wherein each occurrence of Q is independently a bond or is an
optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up
to two non-adjacent methylene units of Q are optionally replaced by
CO, CO.sub.2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO.sub.2,
NRCONR, SO, SO.sub.2, NRSO.sub.2, SO.sub.2NR, NRSO.sub.2NR, O, S,
or NR; and each occurrence of R.sup.5 is independently selected
from R', halogen, NO.sub.2, CN, OR', SR', N(R').sub.2, NR'C(O)R',
NR'C(O)N(R').sub.2, NR'CO.sub.2R', C(O)R', CO.sub.2R', OC(O)R',
C(O)N(R').sub.2, OC(O)N(R').sub.2, SOR', SO.sub.2R',
SO.sub.2N(R').sub.2, NR'SO.sub.2R', NR'SO.sub.2N(R').sub.2,
PO(OR').sub.2, C(O)C(O)R', or C(O)CH.sub.2C(O)R'. In preferred
embodiments, x is 0, 1, 2, or 3. In other preferred embodiments, x
is 1, 2, or 3.
[0099] In preferred embodients, for compounds of formulas I-A-i,
I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, I-E-i, II-A-i,
II-A-ii, II-B-i, II-B-ii, II-C-i, II-C-ii, II-D-i, and II-E-i, Q is
independently a bond or is an optionally substituted
C.sub.1-C.sub.4 alkylidene chain wherein up to two non-adjacent
methylene units of Q are optionally replaced by CO, CO.sub.2, CONR,
OCONR, NRCO, NRCO.sub.2, NRSO.sub.2, SO.sub.2NR, O, S, or NR; and
each occurrence of R.sup.5 is independently selected from R',
halogen, NO.sub.2, CN, OR', SR', N(R').sub.2, NR'C(O)R',
NR'C(O)N(R').sub.2, NR'CO.sub.2R', C(O)R', CO.sub.2R', OC(O)R',
C(O)N(R').sub.2, OC(O)N(R').sub.2, SOR', SO.sub.2R',
SO.sub.2N(R').sub.2, NR'SO.sub.2R', NR'SO.sub.2N(R').sub.2,
PO(OR').sub.2, C(O)C(O)R', or C(O)CH.sub.2C(O)R', and x is 0, 1, 2,
or 3. In preferred embodiments, x is 1, 2, or 3.
[0100] Preferred Q-R.sup.5 substituents on Ar.sup.1 for compounds
of formulas I-A-i, I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i,
I-E-i, II-A-i, II-A-ii, II-B-i, II-B-ii, II-C-i, II-C-ii, II-D-i,
and II-E-i are CH.sub.2halogen, halogen, CH.sub.2CN, CN,
CH.sub.2CO.sub.2R', CO.sub.2R', CH.sub.2COR', COR', R',
CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR', OR', CH.sub.2SR', SR',
haloalkyl, CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or two adjacent occurrences
of Q-R.sup.5, taken together with the atoms to which they are
bound, form an optionally substituted saturated, partially
unsaturated, or fully unsaturated 5-8-membered ring having 0-3
heteroatoms selected from nitrogen, oxygen, or sulfur.
[0101] More preferred Q-R.sup.5 substituents on Ar.sup.1 for
compounds of formulas I-A-i, I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii,
I-D-i, I-E-i, II-A-i, II-A-ii, II-B-i, II-B-ii, II-C-i, II-C-ii,
II-D-i, and II-E-i are fluoro, iodo, chloro, bromo, COCH.sub.3,
CO.sub.2CH.sub.3, C.sub.1-4alkyl (for example, methyl, ethyl,
propyl, cyclopropyl, n-butyl, cyclobuyl, or t-butyl), NH.sub.2,
CH.sub.2NH.sub.2, NHMe, CH.sub.2NHMe, N(Me).sub.2,
CH.sub.2N(Me).sub.2, N(Et).sub.2, CH.sub.2N(Et).sub.2, NH(phenyl),
CO(C.sub.1-4alkyl), CH.sub.2CO(C.sub.1-4alkyl),
NHCO(C.sub.1-4alkyl), CH.sub.2NHCO(C.sub.1-4alkyl), CN, CH.sub.2CN,
OH, C.sub.1-4alkoxy (for example, OCH.sub.3, OCH.sub.2CH.sub.3,
O(CH.sub.2).sub.2CH.sub.3, or O(CH.sub.2).sub.3CH.sub.3),
optionally substituted benzyloxy, optionally substituted phenyloxy,
CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe, optionally substituted
SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl), CONH.sub.2,
CH.sub.2PO(OR').sub.2, or an optionally substituted group selected
from a saturated, partially unsaturated, or fully unsaturated 5- or
6-membered ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. Other preferred Ar.sup.1 substituents
are those substituents where two adjacent occurrences of Q-R.sup.5,
taken together with the atoms to which they are bound, and include
a fused optionally substituted saturated, partially unsaturated, or
fully unsaturated 5- or 6-membered ring having 0-3 heteroatoms
selected from nitrogen, oxygen, or sulfur. In more preferred
embodiments, these fused substituents formed by two adjacent
occurrences of Q-R.sup.5 include an optionally substituted group
selected from methylenedioxy, ethylenedioxy, propylenedioxy,
thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, phenyl,
pyridyl, pyrimidinyl, furyl, thiophene, pyran, pyrrolidinyl,
piperidinyl, piperazinyl, or morpholinyl.
[0102] In yet other embodiments, Ar.sup.1 is phenyl and is
substituted with two occurrences (x=2) of Q-R.sup.5 and Ar.sup.1
is: 19
[0103] wherein each occurrence of QR.sup.5 is independently
CH.sub.2halogen, halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R',
CO.sub.2R', CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2,
CH.sub.2OR', OR', CH.sub.2SR', SR', haloalkyl,
CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2, In certain preferred
embodiments, each occurrence of QR.sup.5 is independently fluoro,
iodo, chloro, bromo, COCH.sub.3, CO.sub.2CH.sub.3, C.sub.1-4alkyl
(for example, methyl, ethyl, propyl, cyclopropyl, n-butyl,
cyclobuyl, or t-butyl), NH.sub.2, CH.sub.2NH.sub.2, NHMe,
CH.sub.2NHMe, N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2,
CH.sub.2N(Et).sub.2, NH(phenyl), CO(C.sub.1-4alkyl),
CH.sub.2CO(C.sub.1-4alkyl), NHCO(C.sub.1-4alkyl),
CH.sub.2NHCO(C.sub.1-4alkyl), CN, CH.sub.2CN, OH, C.sub.1-4alkoxy
(for example, OCH.sub.3, OCH.sub.2CH.sub.3,
O(CH.sub.2).sub.2CH.sub.3, or O(CH.sub.2).sub.3CH.sub.3),
optionally substituted benzyloxy, optionally substituted phenyloxy,
CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe, optionally substituted
SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl), CONH.sub.2,
CH.sub.2PO(OR').sub.2, or an optionally substituted group selected
from a saturated, partially unsaturated, or fully unsaturated 5- or
6-membered ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. In still other preferred embodiments,
both occurrences of QR.sup.5 are methyl. In yet other preferred
embodiments, at least one occurrence of QR.sup.5 is CF.sub.3.
[0104] In yet other embodiments, Ar.sup.1 is phenyl and is
substituted with three occurrences (x=3) of Q-R.sup.5 and Ar.sup.1
is: 20
[0105] wherein each occurrence of QR.sup.5 is independently
CH.sub.2halogen, halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R',
CO.sub.2R', CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2,
CH.sub.2OR', OR', CH.sub.2SR', SR', haloalkyl,
CH.sub.2SO.sub.2N(R').sub.2, SO.sub.2N(R').sub.2,
CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR', CH.sub.2NHCOR',
CH.sub.2PO(OR').sub.2, PO(OR').sub.2. In certain preferred
embodiments, each occurrence of QR.sup.5 is independently fluoro,
iodo, chloro, bromo, COCH.sub.3, CO.sub.2CH.sub.3, C.sub.1-4alkyl
(for example, methyl, ethyl, propyl, cyclopropyl, n-butyl,
cyclobuyl, or t-butyl), NH.sub.2, CH.sub.2NH.sub.2, NHMe,
CH.sub.2NHMe, N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2,
CH.sub.2N(Et).sub.2, NH(phenyl), CO(C.sub.1-4alkyl),
CH.sub.2CO(C.sub.1-4alkyl), NHCO(C.sub.1-4alkyl),
CH.sub.2NHCO(C.sub.1-4alkyl), CN, CH.sub.2CN, OH, C.sub.1-4alkoxy
(for example, OCH.sub.3, OCH.sub.2CH.sub.3,
O(CH.sub.2).sub.2CH.sub.3, or O(CH.sub.2).sub.3CH.sub.3),
optionally substituted benzyloxy, optionally substituted phenyloxy,
CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe, optionally substituted
SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl), CONH.sub.2,
CH.sub.2PO(OR').sub.2, or an optionally substituted group selected
from a saturated, partially unsaturated, or fully unsaturated 5- or
6-membered ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, or sulfur. In still other preferred embodiments,
each occurrence of QR.sup.5 is independently fluoro, iodo, chloro,
bromo, COCH.sub.3, CO.sub.2CH.sub.3, C.sub.1-4alkyl (for example,
methyl, ethyl, propyl, cyclopropyl, n-butyl, cyclobuyl, or
t-butyl), NH.sub.2, CH.sub.2NH.sub.2, NHMe, CH.sub.2NHMe,
N(Me).sub.2, CH.sub.2N(Me).sub.2, N(Et).sub.2, CH.sub.2N(Et).sub.2,
NH(phenyl), CO(C.sub.1-4alkyl), CH.sub.2CO(C.sub.1-4alkyl),
NHCO(C.sub.1-4alkyl), CH.sub.2NHCO(C.sub.1-4a- lkyl), CN,
CH.sub.2CN, OH, optionally substituted benzyloxy, optionally
substituted phenyloxy, CF.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHMe,
optionally substituted SO.sub.2(phenyl), SO.sub.2(C.sub.1-4alkyl),
CONH.sub.2, CH.sub.2PO(OR').sub.2, or an optionally substituted
group selected from a saturated, partially unsaturated, or fully
unsaturated 5- or 6-membered ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0106] Each of the Q-R.sup.5 substituents described above are also
optionally further substituted with one or more groups
independently selected from R, OR, N(R').sub.2, SO.sub.2R, halogen,
NO.sub.2, CN, SR, SO.sub.2N(R').sub.2, CO.sub.2R, C(O)R, or oxo. In
more preferred embodiments, each of the Q-R.sup.5 groups described
above are also optionally further substituted with one or two
groups independently selected from methyl, ethyl, t-butyl, fluoro,
chloro, bromo, oxo, CF.sub.3, OMe, OEt, CN, SO.sub.2Me,
SO.sub.2NH.sub.2, NH.sub.2, NHMe, N(Me).sub.2, SMe, SEt, OH,
C(O)Me, NO.sub.2, or CH.sub.2OH.
[0107] Preferred R.sup.1 and R.sup.2 groups for compounds of
formulas I-A-i, I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, I-E-i,
II-A-i, II-A-ii, II-B-i, II-B-ii, II-C-i, II-C-ii, II-D-i, and
II-E-i are selected from hydrogen, N(R').sub.2, SR, OR, or TR, or
R.sup.1 and R.sup.2, taken together form an optionally substituted
saturated, partially unsaturated, or fully unsaturated 5-membered
ring having 0-2 heteroatoms independently selected from N, O, or S.
More preferred R.sup.1 and R.sup.2 groups are hydrogen, OH,
CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3, CH.sub.2OH,
CH.sub.2OCH.sub.3, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3, NH.sub.2,
or CH.sub.2NH.sub.2, or R.sup.1 and R.sup.2, taken together, form a
fused optionally substituted pyrrolyl, pyrazolyl, or imidazolyl
ring. Still other preferred groups include hydrogen, NH.sub.2, or
CH.sub.2NH.sub.2.
[0108] Preferred R.sup.3 groups of for compounds of formulas I-A-i
and II-A-i are those wherein Z is a bond or is an optionally
substituted C.sub.0-4 alkylidene chain wherein one methylene unit
of Z is optionally replaced by O, NR, NRCO, NRCO.sub.2, NRSO.sub.2,
CONR, C(O), C(O)O, and wherein R.sup.7 is selected from halogen,
CN, N(R').sub.2, NHCOR', or R'. In more preferred embodiments,
R.sup.3 is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1. In most preferred embodiments, R.sup.3
is hydrogen or methyl.
[0109] Preferred R.sup.4 groups of for compounds of formulas I-A-ii
and II-A-ii are those wherein Z is a bond or is an optionally
substituted C.sub.0-4 alkylidene chain wherein one methylene unit
of Z is optionally replaced by O, NR, NRCO, NRCO.sub.2, NRSO.sub.2,
CONR, C(O), C(O)O, and wherein R.sup.7 is selected from halogen,
CN, N(R').sub.2, NHCOR', or R'. In more preferred embodiments,
R.sup.4 is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1. In still other preferred embodiments,
R.sup.4 is hydrogen or methyl.
[0110] Preferred R.sup.3 groups of for compounds of formulas I-B-i
and II-B-i are those wherein Z is a bond or is an optionally
substituted C.sub.0-4 alkylidene chain wherein one methylene unit
of Z is optionally replaced by O, NR, NRCO, NRCO.sub.2, NRSO.sub.2,
CONR, C(O), C(O)O, and wherein R.sup.7 is selected from halogen,
CN, N(R').sub.2, NHCOR', or R'. In more preferred embodiments,
R.sup.3 is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1. In most preferred embodiments, R.sup.3
is hydrogen or methyl.
[0111] Preferred R.sup.4 groups of for compounds of formulas I-B-ii
and II-B-ii are those wherein Z is a bond or is an optionally
substituted C.sub.0-4 alkylidene chain wherein one methylene unit
of Z is optionally replaced by O, NR, NRCO, NRCO.sub.2, NRSO.sub.2,
CONR, C(O), C(O)O, and wherein R.sup.7 is selected from halogen,
CN, N(R').sub.2, NHCOR', or R'. In more preferred embodiments,
R.sup.4 is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1. In still other preferred embodiments,
R.sup.4 is hydrogen or methyl.
[0112] Preferred R.sup.3 groups of for compounds of formulas I-C-i
and II-C-i are those wherein Z is a bond or is an optionally
substituted C.sub.0-4 alkylidene chain wherein one methylene unit
of Z is optionally replaced by O, NR, NRCO, NRCO.sub.2, NRSO.sub.2,
CONR, C(O), C(O)O, and wherein R.sup.7 is selected from halogen,
CN, N(R').sub.2, NHCOR', or R'. In more preferred embodiments,
R.sup.3 is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1. In most preferred embodiments, R.sup.3
is hydrogen or methyl.
[0113] Preferred R.sup.4 groups of for compounds of formulas I-C-ii
and II-C-ii are those wherein Z is a bond or is an optionally
substituted C.sub.0-4 alkylidene chain wherein one methylene unit
of Z is optionally replaced by O, NR, NRCO, NRCO.sub.2, NRSO.sub.2,
CONR, C(O), C(O)O, and wherein R.sup.7 is selected from halogen,
CN, N(R').sub.2, NHCOR', or R'. In more preferred embodiments,
R.sup.4 is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1. In still other preferred embodiments,
R.sup.4 is hydrogen or methyl.
[0114] In still other preferred embodiments, for each of the
embodiments described directly above n is 0. In yet other preferred
embodiments, for each of the embodiments described directly above n
is 1.
[0115] In still other preferred embodiments, for compounds of
formulas I-E-i and II-E-i, where R.sup.3 and R.sup.4, taken
together with the atoms to which they are bound, form an optionally
substituted phenyl ring optionally substituted with 0, 1, 2, 3, 4,
or 5 occurrences of Y--R.sup.8, each occurrence of Y--R.sup.8 is
independently methyl, ethyl, t-butyl, fluoro, chloro, bromo, oxo,
CF.sub.3, OMe, OEt, CN, SO.sub.2Me, SO.sub.2NH.sub.2, NH.sub.2,
NHMe, N(Me).sub.2, SMe, SEt, OH, C(O)Me, NO.sub.2, or CH.sub.2OH.
In preferred embodiments, q is 0, 1, or 2.
[0116] In yet other preferred embodiments compounds have one of
formulas II-A-i, Il-B-i, or II-C-i, wherein the compound variables
are defined as:
[0117] a) x is 0, 1, 2, or 3 and Q-R.sup.5 is CH.sub.2halogen,
halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R', CO.sub.2R',
CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR',
OR', CH.sub.2SR', SR', haloalkyl, CH.sub.2SO.sub.2N(R').sub.2,
SO.sub.2N(R').sub.2, CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR',
CH.sub.2NHCOR', CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or Q-R.sup.5,
taken together with the atoms to which they are bound, form an
optionally substituted saturated, partially unsaturated, or fully
unsaturated 5-8-membered ring having 0-3 heteroatoms selected from
nitrogen, oxygen, or sulfur;
[0118] b) R.sup.1 and R.sup.2 are each independently hydrogen,
N(R').sub.2, SR, OR, or TR, or R.sup.1 and R.sup.2, taken together
form an optionally substituted saturated, partially unsaturated, or
fully unsaturated 5-membered ring having 0-2 heteroatoms
independently selected from N, O, or S; and
[0119] c) R.sup.3 is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1.
[0120] In yet other preferred embodiments compounds have one of
formulas II-A-ii, II-B-ii, or II-C-ii, wherein one or more of the
compound variables are defined as:
[0121] a) x is 0, 1, 2, or 3, and Q-R.sup.5 is CH.sub.2halogen,
halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R', CO.sub.2R',
CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR',
OR', CH.sub.2SR', SR', haloalkyl, CH.sub.2SO.sub.2N(R').sub.2,
SO.sub.2N(R').sub.2, CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR',
CH.sub.2NHCOR', CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or Q-R.sup.5,
taken together with the atoms to which they are bound, form an
optionally substituted saturated, partially unsaturated, or fully
unsaturated 5-8-membered ring having 0-3 heteroatoms selected from
nitrogen, oxygen, or sulfur;
[0122] b) R.sup.1 and R.sup.2 are each independently hydrogen,
N(R').sub.2, SR, OR, or TR, or R.sup.1 and R.sup.2 taken together
form an optionally substituted saturated, partially unsaturated, or
fully unsaturated 5-membered ring having 0-2 heteroatoms
independently selected from N, O, or S; and
[0123] c) R.sup.4 is (CH.sub.2).sub.nhalogen, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nOR.sup.7, (CH.sub.2).sub.nNRR.sup.7,
(CH.sub.2).sub.nC(O)R.sup.7, (CH.sub.2).sub.nC(O)R.sup.7
(CH.sub.2).sub.nCH.sub.3, (CH.sub.2).sub.nC(O)NRR.sup.7,
(CH.sub.2).sub.nSR.sup.7, wherein R.sup.7 is
(CH.sub.2).sub.mN(R').sub.2, C.sub.1-C.sub.4alkyl, an optionally
substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or
heteroaralkyl group, or R and R.sup.7, taken together with the
nitrogen atom to which they are bound form an optionally
substituted 3-8-membered saturated or partially unsaturated ring
having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n
is 0 or 1, and m is 0 or 1.
[0124] In yet other preferred embodiments compounds have formula
II-E-i, wherein one or more of the compound variables are defined
as:
[0125] a) x is 0, 1, 2, or 3, and Q-R.sup.5 is CH.sub.2halogen,
halogen, CH.sub.2CN, CN, CH.sub.2CO.sub.2R', CO.sub.2R',
CH.sub.2COR', COR', R', CH.sub.2NO.sub.2, NO.sub.2, CH.sub.2OR',
OR', CH.sub.2SR', SR', haloalkyl, CH.sub.2SO.sub.2N(R').sub.2,
SO.sub.2N(R').sub.2, CH.sub.2N(R').sub.2, N(R').sub.2, NHCOR',
CH.sub.2NHCOR', CH.sub.2PO(OR').sub.2, PO(OR').sub.2, or Q-R.sup.5,
taken together with the atoms to which they are bound, form an
optionally substituted saturated, partially unsaturated, or fully
unsaturated 5-8-membered ring having 0-3 heteroatoms selected from
nitrogen, oxygen, or sulfur;
[0126] b) R.sup.1 and R.sup.2 are each independently hydrogen,
N(R').sub.2, SR, OR, or TR, or R.sup.1 and R.sup.2, taken together
form an optionally substituted saturated, partially unsaturated, or
fully unsaturated 5-membered ring having 0-2 heteroatoms
independently selected from N, O, or S; and
[0127] c) q is 0, 1, or 2, and each occurrence of Y--R.sup.8 is
independently methyl, ethyl, t-butyl, fluoro, chloro, bromo, oxo,
CF.sub.3, OMe, OEt, CN, SO.sub.2Me, SO.sub.2NH.sub.2, NH.sub.2,
NHMe, N(Me).sub.2, SMe, SEt, OH, C(O)Me, NO.sub.2, or
CH.sub.2OH.
[0128] Exemplary compounds of Formula I (and classes and subclasses
thereof) are depicted in Table 1 below:
[0129] Table 1. Examples of Compounds of Formula I:
2122232425262728293031323334353637383940414243444546474849505152535455565-
75859606162636465666768697071727374757677787980818283848586878889
[0130] 4. General Synthetic Methodology:
[0131] The compounds of this invention may be prepared in general
by methods known to those skilled in the art for analogous
compounds, as illustrated by the general scheme below, and the
preparative examples that follow.
[0132] Scheme I below shows a general synthetic route that may be
used used for preparing compounds of formula I. 90
[0133] Reagents and conditions: (a) DMF-DMA, THF, 12-18 hours, room
temperature; (b) Ethanol, reflux, 12-18 hours.
[0134] In step (a), a solution of 2-acetyl thiazole A in TBF is
treated with dimethylformamide-dimethylacetal and the resulting
mixture stirred at room temperature over night. The reaction
mixture is concentrated in vacuo and the concentrate triturated
with diethyl ether to afford B.
[0135] To prepare intermediate C, a mixture of Ar.sup.1NH.sub.2 and
cyanamide in HCl (4N in dioxane) is heated at 120.degree. C.
overnight. After cooling to room temperature, aqueous work-up
affords the desired guanidine compound C. One of skill in the art
would recognize that a wide variety of aryl guanidines may be
prepared and may thus be used to prepare compounds of formula I
with a wide variety of Ar.sup.1 rings.
[0136] In step (b), guanidine C is combined with enaminone B in
ethanol in a sealed tube. The resulting mixture is heated at reflux
overnight then concentrated and the crude product purified by
column chromatography to afford the desired pyrimidine compound I.
The details of the conditions used for producing these compounds
are set forth in the Examples.
[0137] In one exemplary embodiment, phenylguanidine C-i is prepared
and used to generate compounds of general formula II, as depicted
generally below. 91
[0138] Schemes III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII
below depict the synthesis of certain exemplary compounds of the
invention.
[0139] Scheme III below depicts the synthesis of exemplary
compounds where R.sup.3 or R.sup.4 is CH.sub.2OH or
CH.sub.2NRR.sup.7: 9293
[0140] Scheme IV below depicts the synthesis of exemplary compounds
where R.sup.3 is CN or CH.sub.2Br. 94
[0141] Scheme V depicts the synthesis of exemplary compounds where
R.sup.3 is CH.sub.2OMe or CH.sub.2CN. 95
[0142] Scheme VI depicts the synthesis of exemplary compounds where
R.sup.3 is CH.sub.2COOH. 96
[0143] Scheme VII below depicts the synthesis of exemplary
compounds where both R.sup.3 and R.sup.4 are substituted (as
depicted, where R.sup.3 is Me and R.sup.4 is (CH.sub.2).sub.2OH).
97
[0144] Schemes VIII and IX below depict the synthesis of exemplary
compounds where both R.sup.3 and R.sup.4 are substituted (as shown,
where both R.sup.3 and R.sup.4 are methyl). 98 99
[0145] Schemes X, and XI below depict the synthesis of exemplary
compounds where one of R.sup.3 or R.sup.4 is hydrogen and the other
of R.sup.3 or R.sup.4 is NRR.sup.7. For both Schemes X and XI
reaction conditions are as follows: (a) n-BuLi, ethylacetate; (b)
PTSA, HC(OMe).sub.3, MeOH; (c) n-BuLi, CCl4; (d) TFA, DCM; (e)
DMF.DMA; (f) EPA, NaOH; (g) piperazine, DMSO; (h) ethylene diamine;
(i) n-BuLi, CBr.sub.4. 100 101
[0146] Schemes XII, and XIII below depict the synthesis of
exemplary compounds where R.sup.3 and R.sup.4 are taken together to
form an optionally substituted saturated, partially unsaturated, or
Fully unsaturated 3-8-membered ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In certain
exemplary embodiments, as depicted below, R.sup.3 and R.sup.4 are
taken together to form an optionally substituted phenyl ring. 102
103
[0147] Although certain exemplary embodiments are depicted and
described above and herein, it will be appreciated that additional
compounds of the invention can be prepared according to the methods
described generally above using appropriate starting materials by
methods generally available to one of ordinary skill in the
art.
[0148] 5. Uses, Formulation and Administration
[0149] Pharmaceutically Acceptable Compositions
[0150] As discussed above, the present invention provides compounds
that are inhibitors of protein kinases, and thus the present
compounds are useful for the treatment of diseases, disorders, and
conditions including, but not limited to immunodeficiency
disorders, inflammatory diseases, allergic diseases, autoimmune
diseases, proliferative disorders, immunologically-mediated
diseases, or respiratory disorders. Accordingly, in another aspect
of the present invention, pharmaceutically acceptable compositions
are provided, wherein these compositions comprise any of the
compounds as described herein, and optionally comprise a
pharmaceutically acceptable carrier, adjuvant or vehicle. In
certain embodiments, these compositions optionally further comprise
one or more additional therapeutic agents.
[0151] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable salts, esters, salts of such esters, or any other adduct
or derivative which upon administration to a patient in need is
capable of providing, directly or indirectly, a compound as
otherwise described herein, or a metabolite or residue thereof.
[0152] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof. As used herein,
the term "inhibitorily active metabolite or residue thereof" means
that a metabolite or residue thereof is also an inhibitor of SYK or
ZAP-70 kinase.
[0153] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al., describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonat- e, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0154] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0155] Uses of Compounds and Pharmaceutically Acceptable
Compositions
[0156] In yet another aspect, a method for the treatment or
lessening the severity of immunodeficiency disorders, inflammatory
diseases, allergic diseases, autoimmune diseases, proliferative
disorders, immunologically-mediated diseases, or respiratory
disorders is provided comprising administering an effective amount
of a compound, or a pharmaceutically acceptable composition
comprising a compound to a subject in need thereof. In certain
embodiments of the present invention an "effective amount" of the
compound or pharmaceutically acceptable composition is that amount
effective for treating or lessening the severity of
immunodeficiency disorders, inflammatory diseases, allergic
diseases, autoimmune diseases, proliferative disorders,
immunologically-mediated diseases, or respiratory disorders. The
compounds and compositions, according to the method of the present
invention, may be administered using any amount and any route of
administration effective for treating or lessening the severity of
immunodeficiency disorders, inflammatory diseases, allergic
diseases, autoimmune diseases, proliferative disorders,
immunologically-mediated diseases, or respiratory disorders. The
exact amount required will vary from subject to subject, depending
on the species, age, and general condition of the subject, the
severity of the infection, the particular agent, its mode of
administration, and the like. The compounds of the invention are
preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of
agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular patient or
organism will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed, and like
factors well known in the medical arts. The term "patient", as used
herein, means an animal, preferably a mammal, and most preferably a
human.
[0157] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments,
the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0158] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0159] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0160] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0161] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0162] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0163] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0164] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0165] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0166] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0167] As described generally above, the compounds of the invention
are useful as inhibitors of protein kinases. In one embodiment, the
compounds and compositions of the invention are inhibitors of one
or more of SYK or ZAP-70, and thus, without wishing to be bound by
any particular theory, the compounds and compositions are
particularly useful for treating or lessening the severity of a
disease, condition, or disorder where activation of one or more of
SYK or ZAP-70 is implicated in the disease, condition, or disorder.
When activation of SYK or ZAP-70 is implicated in a particular
disease, condition, or disorder, the disease, condition, or
disorder may also be referred to as "SYK or ZAP-70-mediated
disease" or disease symptom. Accordingly, in another aspect, the
present invention provides a method for treating or lessening the
severity of a disease, condition, or disorder where activation or
one or more of SYK or ZAP-70 is implicated in the disease
state.
[0168] The activity of a compound utilized in this invention as an
inhibitor of SYK or ZAP-70, may be assayed in vitro, in vivo or in
a cell line. In vitro assays include assays that determine
inhibition of either the phosphorylation activity or ATPase
activity of activated SYK or ZAP-70. Alternate in vitro assays
quantitate the ability of the inhibitor to bind to SYK or ZAP-70.
Inhibitor binding may be measured by radiolabelling the inhibitor
prior to binding, isolating the inhibitor/SYK or inhibitor/ZAP-70,
complex and determining the amount of radiolabel bound.
Alternatively, inhibitor binding may be determined by running a
competition experiment where new inhibitors are incubated with SYK
or ZAP-70 bound to known radioligands.
[0169] The term "measurably inhibit", as used herein means a
measurable change in SYK or ZAP-70 activity between a sample
comprising said composition and a SYK or ZAP-70 kinase and an
equivalent sample comprising SYK or ZAP-70 kinase in the absence of
said composition.
[0170] The term "SYK-mediated disease" or "SYK-mediated condition",
as used herein, means any disease or other deleterious condition in
which SYK protein kinase is known to play a role. Such conditions
include, without limitation, allergic disorders, especially
asthma.
[0171] The term "ZAP-70-mediated condition", as used herein means
any disease or other deleterious condition in which ZAP-70 is known
to play a role. Such conditions include, without limitation,
autoimmune, inflammatory, proliferative, and hyperproliferative
diseases and immunologically-mediated diseases including rejection
of transplanted organs or tissues and Acquired Immunodeficiency
Syndrome (AIDS).
[0172] For example, ZAP-70-mediated conditions include diseases of
the respiratory tract including, without limitation, reversible
obstructive airways diseases including asthma, such as bronchial,
allergic, intrinsic, extrinsic and dust asthma, particularly
chronic or inveterate asthma (e.g. late asthma airways
hyper-responsiveness) and bronchitis. Additionally, ZAP-70 diseases
include, without limitation, those conditions characterised by
inflammation of the nasal mucus membrane, including acute rhinitis,
allergic, atrophic thinitis and chronic rhinitis including rhinitis
caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca
and rhinitis medicamentosa; membranous rhinitis including croupous,
fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis,
seasonal rhinitis including rhinitis nervosa (hay fever) and
vasomotor rhinitis, sarcoidosis, farmer's lung and related
diseases, fibroid lung and idiopathic interstitial pneumonia.
[0173] ZAP-70-mediated conditions also include diseases of the bone
and joints including, without limitation, (pannus formation in)
rheumatoid arthritis, seronegative spondyloarthropathis (including
ankylosing spondylitis, psoriatic arthritis and Reiter's disease),
Behcet's disease, Sjogren's syndrome, and systemic sclerosis.
[0174] ZAP-70-mediated conditions also include diseases and
disorders of the skin, including, without limiation, psoriasis,
systemic sclerosis, atopical dermatitis, contact dermatitis and
other eczematous dermatitis, seborrhoetic dermatitis, Lichen
planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa,
urticaria, angiodermas, vasculitides, erythemas, cutaneous
eosinophilias, uveitis, Alopecia, greata and vernal
conjunctivitis.
[0175] ZAP-70-mediated conditions also include diseases and
disorders of the gastrointestinal tract, including, without
limitation, Coeliac disease, proctitis, eosinophilic
gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease,
ulcerative colitis, food-related allergies which have effects
remote from the gut, e.g. migraine, rhinitis and eczema.
[0176] ZAP-70-mediated conditions also include those diseases and
disorders of other tissues and systemic disease, including, without
limiation, multiple sclerosis, artherosclerosis, acquired
immunodeficiency syndrome (AIDS), lupus erythematosus, systemic
lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis,
type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper
IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic
thrombocytopenia purpura, restenosis following angioplasty, tumours
(for example leukemia, lymphomas), artherosclerosis, and systemic
lupus erythematosus.
[0177] ZAP-70-mediated conditions also include allograft rejection
including, without limitation, acute and chronic allograft
rejection following for example transplantation of kidney, heart,
liver, lung, bone marrow, skin and cornea; and chronic graft versus
host disease.
[0178] It will also be appreciated that the compounds and
pharmaceutically acceptable compositions of the present invention
can be employed in combination therapies, that is, the compounds
and pharmaceutically acceptable compositions can be administered
concurrently with, prior to, or subsequent to, one or more other
desired therapeutics or medical procedures. The particular
combination of therapies (therapeutics or procedures) to employ in
a combination regimen will take into account compatibility of the
desired therapeutics and/or procedures and the desired therapeutic
effect to be achieved. It will also be appreciated that the
therapies employed may achieve a desired effect for the same
disorder (for example, an inventive compound may be administered
concurrently with another agent used to treat the same disorder),
or they may achieve different effects (e.g., control of any adverse
effects). As used herein, additional therapeutic agents that are
normally administered to treat or prevent a particular disease, or
condition, are known as "appropriate for the disease, or condition,
being treated".
[0179] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0180] The compounds of this invention or pharmaceutically
acceptable compositions thereof may also be incorporated into
compositions for coating implantable medical devices, such as
prostheses, artificial valves, vascular grafts, stents and
catheters. Accordingly, the present invention, in another aspect,
includes a composition for coating an implantable device comprising
a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for
coating said implantable device. In still another aspect, the
present invention includes an implantable device coated with a
composition comprising a compound of the present invention as
described generally above, and in classes and subclasses herein,
and a carrier suitable for coating said implantable device.
[0181] Vascular stents, for example, have been used to overcome
restenosis (re-narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk clot
formation or platelet activation. These unwanted effects may be
prevented or mitigated by pre-coating the device with a
pharmaceutically acceptable composition comprising a kinase
inhibitor. Suitable coatings and the general preparation of coated
implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol,
polylactic acid, ethylene vinyl acetate, and mixtures thereof. The
coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids
or combinations thereof to impart controlled release
characteristics in the composition.
[0182] Another aspect of the invention relates to inhibiting SYK or
ZAP-70 activity in a biological sample or a patient, which method
comprises administering to the patient, or contacting said
biological sample with a compound of formula I or a composition
comprising said compound. The term "biological sample", as used
herein, includes, without limitation, cell cultures or extracts
thereof; biopsied material obtained from a mammal or extracts
thereof; and blood, saliva, urine, feces, semen, tears, or other
body fluids or extracts thereof.
[0183] Inhibition of SYK or ZAP-70 kinase activity in a biological
sample is useful for a variety of purposes that are known to one of
skill in the art. Examples of such purposes include, but are not
limited to, blood transfusion, organ-transplantation, biological
specimen storage, and biological assays.
EXAMPLES
[0184] A) Synthesis of Exemplary Compounds of the Invention:
Example 1
[0185] 1-(4-Methyl-thiazol-2-yl)-ethanone (2a).
[0186] To a stirred solution of n-BuLi (2M in pentane; 22.4 mL,
0.045 mol) in 70 mL of dry ether at -78.degree. C. was added
dropwise 4-methylthiazole (3.7 g, 0.037 mol) in 30 mL of ether over
a period of 30 minutes. The mixture was stirred for 1 h, then
N-methoxy-N-methylacetamid- e (4.37 mL, 0.041 mol) was added
dropwise over 10 minutes. After 1 h of stirring at -78.degree. C.
the reaction mixture was washed with sat'd NaHCO.sub.3 and
extracted with ether. The organic layer was dried with
Na.sub.2SO.sub.4 and concentrated in vacuo to give 4.38 g (85%) of
2a as an oil that was used directly for the next step. .sup.1H NMR
(CDCl.sub.3) .delta. 7.2 (s, 1H), 2.75 (s, 3H), 2.5 (s, 3H).
[0187] 1-(4-Bromomethyl-thiazol-2-yl)-ethanone (3a).
[0188] A solution of 2a (4.38 g, 0.031 mol), NBS (5.8 g, 0.033 mol)
and 100 mg of AIBN in 40 mL of carbon tetrachloride was heated at
70.degree. C. for 16 h. Cooled to rt and the precipitate was
filtered. The solvent was concentrated in vacuo to an oil that was
subjected to flash chromatography (5% ethyl acetate/95% hexanes) to
give 4.95 g (72%) of the desired product 3a. .sup.1H NMR
(CDCl.sub.3) .delta. 7.8 (s, 1H), 4.8 (s, 2H), 2.8 (s, 3H).
[0189] Acetic acid 2-acetyl-thiazol-4-ylmethyl ester (4a).
[0190] Bromide 3a (4.95 g, 0.0224 mol) was heated with acetic acid
(50 mL) and potassium acetate (2.64 g, 0.0269 mol) at 100.degree.
C. for 16 h. Diluted with ethyl acetate and washed with water 3
times. The organic layer was dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to give a crude oil that was subjected to
flash chromatography (20% ethyl acetate/80% hexanes) to give 2.48 g
(70%) of the desired product 4a. .sup.1H NMR (CDCl.sub.3) .delta.
7.8 (s, 1H), 5.2 (s, 2H), 2.8 (s, 3H), 2.2 (s, 3H).
[0191] 3-Dimethylamino-1-(4-hydroxymethyl-thiazol-2-yl)-propenone
(5a).
[0192] A solution of 4a (2.48 g, 0.124 mol) in 8.3 mL of DMF-DMA
was heated at 90.degree. C. in a sealed tube for 16 h. The
precipitate that formed upon cooling was collected to give 2 g
(76%) of the desired enaminone 5a. .sup.1H NMR (CDCl.sub.3) .delta.
7.8 (bs, 1H), 7.2 (s, 1H), 6.1 (bs, 1H), 4.8 (s, 2H), 3.1 (s, 3H),
2.9 (s, 3H).
[0193]
{2-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-thiazol-4-yl}-meth-
anol (7a).
[0194] Guanidine 6 (868 mg, 0.0041 mol) and enaminone 5a (1 g,
0.0061 mol) were mixed together with potassium carbonate (596 mg,
0.0011 mol) in 2 mL of DMF and heated at 90.degree. C. in a sealed
tube for 16 h. Cooled and diluted with ethyl acetate and washed
several time with water (3.times.) and brine. The organic layer was
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to a solid
residue that was subjected to flash chromatography (10%
methanol/90% dichloromethane) to give 1.14 g (89%) of the desired
pyrimidine 7. .sup.1H NMR (CDCl.sub.3) .delta. 8.4 (d, 1H), 7.9
(bs, 1H), 7.4 (d, 1H), 7.3 (s, 1H), 6.8 (s, 1H), 4.8 (s, 2H), 2.2
(6H).
Example 2
[4-(4-Alkylaminomethyl-thiazol-2-yl)-pyrimidin-2-yl]-(3,5-dimethyl-phenyl)-
-amine (8a).
[0195] To a solution of 7a (125 mg, 0.4 mmol) in 10 mL of anhydrous
DCM was added mesyl chloride (93 uL, 1.2 mmol) followed by
trietylamine. TLC showed the disapearance of 7 after 5 minutes. The
reaction mixture was partitioned between DCM and water. The organic
was washed with water and dried (Na.sub.2SO.sub.4) and concentrated
in vacuo to an oil that was used directly for the mesylate
displacement by amines. The crude mesylate was dissolved in DCM and
partitioned in 5 sealed test tubes and reacted with excess of
amines for 16 h. The samples were blown down to dryness and
dissolved in 1 mL DMSO and purified by reverse phase prep. HPLC
(Water-MeCN; 10%-90%) with 0.1% TFA to give -30 mg of amines 8a TFA
salts after lyophylization.
Example 3
2-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-thiazole-4-carbaldehyde
(9a).
[0196] To a solution of 7a (100 mg, 0.320 mmol) and 163 uL of
t-butanol in 2 mL of DCM was added 163 mg of Dess_Martin
periodinane reagent. The reaction mixture was stirred for 1 h after
which it was quenched with sodium thiosulfate (1 mL). It was
stirred until the two phase became clear. The organic layer was
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give 35 mg
(38%) the crude aldehyde 9a that was used directly for the next
step. .sup.1H NMR (CDCl.sub.3) .delta. 10.1 (s, 1H), 8.3 (d, 1H),
8.1 (s, 1H), 7.5 (d, 1H), 7.2 (s, 2H), 6.8 (s, 1H), 2.3 (s,
6H).
[0197]
2-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-thiazole-4-carbonit-
rile (10a).
[0198] To a stirring solution of the crude aldehyde 9a (35 mg, 0.11
mmol) in 1 mL of ammonia water 28% solution and 0.1 mL of THF at rt
was added iodine (32 mg, 0.12 mmol). The dark solution became
colorless after 1 h of stirring. The reaction mixture was
neutralized with 0.5 mL of a 1M aqueous solution of HCl and
extracted with ether. Concentrated in vacuo and passed through a
short pad of silica gel (30% ethyl acetate/70% hexanes) to give 20
mg (59%) of pure 10.
Example 4
[4-(4-Bromomethyl-thiazol-2-yl)-pyrimidin-2-yl]-(3,5-dimethyl-phenyl)-amin-
e (11a).
[0199] Triphenylphosphine (84 mg, 0.38 mmol) in DCM was added
dropwise to a solution of alcohol 7 (100 mg, 0.32 mmol) and carbon
tetrabromide (127 mg, 0.38 mmol) in DCM. Afetr 20 minutes of
stirring, the reaction mixture was concentrated in vacuo to a solid
residue that was subjected to flash chromatography (30% ethyl
acetate/70% hexanes) to give 240 mg (67%) of the desired benzylic
bromide 11a.
Example 5
(3,5-Dimethyl-phenyl)-[4-(4-methoxymethyl-thiazol-2-yl)-pyrimidin-2-yl]-am-
ine (12a).
[0200] Benzyl bromide 11a was dissolved in 0.4 mL of a 0.5 M
solution of sodium methoxide in methanol and stirred 16 h at rt.
Concentrated to dryness and patitionned with ethyl acetate and
water. The organic layer was dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to a solid residue. Purified by reverse phase
prep. HPLC (Water-MeCN; 10%-90%) with 0.1% TFA to give 11 mg (34%)
of methoxymethyl ether 12a.
Example 6
{2-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-thiazol-4-yl}-acetonitril-
e (13a).
[0201] To a solution of benzyl bromide 11a (51 mg, 0.135 mmol) in 1
mL of DMF was added potassium cyanide (9 mg, 0.135 mmol) in 0.250
mL of water. The reaction mixture was stirred at rt for 3 h. Two mL
of water was added and the mixture was extracted with ethyl
acetate. The organic phase was dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Purified by reverse phase prep. HPLC
(Water-MeCN; 10%-90%) with 0.1% TFA to give 16 mg (37%) of the
benzyl cyanide 13a.
Example 7
{2-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-thiazol-4-yl}-acetic
acid (14a).
[0202] A solution of the above cyanide 13a was hydrolysed with a
mixture of acetic acid and hydrochloric acid in water at 95.degree.
C. to give crude acid 14a. Purified by reverse phase prep. HPLC
(Water-MeCN; 10%-90%) with 0.1% TFA to give 40 mg (39%) of the
desired product.
Example 8
1-{4-Methyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-thiazol-2-yl}-ethanone
(16).
[0203] To a stirred solution of n-BuLi (2M in pentane; 15.24 mL,
0.0305 mol) in 70 mL of dry ether at -78.degree. C. was added
dropwise 29 (6.3 g, 0.0277 mol) in 30 mL of ether over a period of
30 minutes. The mixture was stirred for 1 h, then
N-methoxy-N-methylacetamide (3.83 mL, 0.036 mol) was added dropwise
over 10 minutes. After 1 h of stirring at -78.degree. C. the
reaction mixture was washed with sat'd NaHCO.sub.3 and extracted
with ether. The organic layer was dried with Na.sub.2SO.sub.4 and
concentrated in vacuo to give 6.66 g (89%) of 16 as an oil that was
used directly for the next step.
[0204]
3-Dimethylamino-1-{4-methyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]--
thiazol-2-yl}-propenone (17).
[0205] A solution of 16 (6.66 g, 0.0247 mol) in 16 mL of DMF-DMA
was heated at 90.degree. C. in a sealed tube for 16 h. The reaction
mixture was concentrated under vacuum to give 8 g (100%) of the
desired enaminone 17 as an orange oil.
[0206]
2-{2-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-
-5-yl}-ethanol (19a).
[0207] Title compound was prepared from enaminone 17 and the
appropriate guanidine in the usual protocol to give the desired
pyrimidine 18a. Deprotection of the THP group with a catalytic
amount of p-toluensulfonic acid in methanol gave, after work up,
the desired alcohol 19a.
Example 9
Preparation of Disubstituted Ar.sup.1 Compounds
[0208] 104
[0209] 3-Nitro-5-trifluoromethyl-phenol 44: To a solution of
1-Methoxy-3-nitro-5-trifluoromethyl-benzene (3.5 g, 15.83 mmol) in
20 ml of CHCl.sub.3 was added a solution of 1M boron tribromide
(23.74 ml, 23.74 mmol) and the reaction was stirred at RT for 3
days resulting in conversion to product by TLC (20% EtOAc:Hexanes).
The reaction was partitioned between CH.sub.2Cl.sub.2/1N NaOH and
extracted. The aqueous phase was acidified with 1N HCl and again
extracted with CH.sub.2Cl.sub.2. The organics were dried over
sodium sulfate and stripped down in vacuo giving
3-Nitro-5-trifluoromethyl-phenol (1.4 g, 6.76 mmol) as a yellow
oil.
[0210] 3-Amino-5-trifluoromethyl-phenol 45: To a solution of
3-Nitro-5-trifluoromethyl-phenol 44 (1.6 g, 7.73 mmol) was added a
catalytic amount of 20% palladium hydroxide on carbon and the
reaction was stirred under a hydrogen atmosphere (balloon) over the
weekend resulting in complete conversion to product by TLC (40%
EtOAc:Hexanes). The reaction was filtered to give
3-Amino-5-trifluoromethyl-phenol (1.2 g, 6.76 mmol) as a brown/red
oil.
[0211] N-(3-Hydroxy-5-trifluoromethyl-phenyl)-guanidine 46: A
solution of 3-Amino-5-trifluoromethyl-phenol (0.21 g, 1.19 mmol),
cyanamide (0.5 g, 1.19 mmol), 4N HCl in dioxane (2.975 ml, 1.199
mmol) in dioxane (10 ml) was heated in a sealed tube at 80.degree.
C. overnight resulting in complete conversion to product by TLC
(10% MeOH:CH.sub.2Cl.sub.2). The reaction was partitioned between
ethyl acetate/saturated NH.sub.4Cl solution and extracted. Some
product remained in the aqueous phase after multiple extractions.
The crude product (0.65 g, 0.297 mmol) was sufficiently pure by
LC/MS to use directly for the next step.
[0212] Subsequent reaction with the appropriate thiazolyl reagent
(using conditions similar to those detailed above and herein),
yields the desired disubstituted Ar.sup.1 compounds. In one
exemplary embodiment, a compound of formula 47 is prepared: 105
Example 10
[4-(5-piperazin-1-yl-thiazol-2-yl)-pyrimidin-2-yl]-(3,4,5-trimethoxy-pheny-
l)-amine
[0213] 106
[0214] Method A:
[0215] 1-Thiazol-2-yl-ethanone 107
[0216] To cooled (-78.degree. C.) diethyl ether (30 ml) was added
n-butyllithium (13.2 ml of 2.5M solution in hexanes), followed by
the dropwise addition of a solution of 2-bromothiazole (2.7 ml) in
diethyl ether (35 ml) over 20 minutes. The resulting mixture was
stirred for 30 minutes at -78.degree. C. Under rapid stirring,
ethylacetate (5 ml) was added over 2-3 minutes. The mixture was
stirred for 30 minutes at -78.degree. C., then allowed to warm to
ambient and quenched with saturated sodium bicarbonate solution (50
ml). More diethyl ether (50 ml) and water (50 ml) was added. The
organic phase was separated, washed with water and brine, dried
with magnesium sulfate, filtered and concentrated. The residue was
purified by flash chromatography (20% ethyl acetate/petroleum
ether) to afford the sub-title compound as a yellow oil (3.3 g,
87%); .sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 2.7 (3H, s), 7.65
(1H, s), 8.0 (1H, s); MS (ES+) 128.1 (M+1).
[0217] Method B:
[0218] 2-(1,1-Dimethoxy-ethyl)-thiazole 108
[0219] To a solution of 1-Thiazol-2-yl-ethanone (7 g) in dry
methanol (100 ml) was added trimethyl orthoformate (35 ml) and
p-toluenesulfonic acid (10 g) and the resulting mixture was heated
at 50.degree. C. for 12 hours. The mixture was cooled to ambient
and concentrated, partitioned between saturated sodium bicarbonate
and diethyl ether (100 ml). The organic phase was removed and
washed with saturated sodium bicarbonate and brine, dried
(magnesium sulfate), filtered and concentrated to afford the
sub-title compound as crude product. The product could be further
purified if necessary by flash chromatography (20% ethyl
acetate/petroleum ether) to afford the sub-title compound in
quantitative yield as yellow oil (9.5 g); .sup.1H NMR (400 Mhz,
CDCl.sub.3) .delta. 1.75 (3H, s), 3.25 (6H, s), 7.3 (1H, s), 7.85
(1H, s); MS (ES+) 174.1 (M+1).
[0220] Method C:
[0221] 5-Chloro-2-(1,1-dimethoxy-ethyl)-thiazole 109
[0222] To a cooled (-78.degree. C.) solution of
2-(1,1-Dimethoxy-ethyl)-th- iazole_(4 g) in THF (60 ml) was added
n-butyllithium (10 ml of 2.5M solution in hexanes) over 5 minutes.
The resulting mixture was stirred for 30 minutes at -78 C, then a
solution of carbon tetrachloride (10 ml) in TBF (30 ml) was added
dropwise over 5 minutes. The resulting mixture was stirred for 30
minutes at -78.degree. C., then allowed to warm up to 0.degree. C.
and quenched with saturated ammonium chloride solution. The mixture
was concentrated, diluted with water (100 ml) and extracted with
diethyl ether (100 ml). The organic phase was removed, washed with
water and brine, dried (magnesium sulfate), filtered and
concentrated. The residue was purified by flash chromatography (10%
ethyl acetate/petroleum ether) to afford the sub-titled compound as
a yellow solid (3.6 g, 69%); .sup.1H NMR (400 Mhz, CDCl.sub.3)
.delta. 1.70 (3H, s), 3.25 (6H, s), 7.6 (1H, s).
[0223] Method D:
[0224] 1-(5-Chloro-thiazol-2-yl)-ethanone 110
[0225] To a solution of 5-Chloro-2-(1,1-dimethoxy-ethyl)-thiazole
(3.5 g) in dichloromethane (20 ml) was added trifluoroacetic acid
(30 ml) and water (1 ml). The resulting mixture was stirred
overnight at ambient, concentrated to an oil, diluted with diethyl
ether, washed with 10% sodium bicarbonate, water and brine, dried
(magnesium sulfate), filtered and concentrated to afford the
sub-titled compound as a yellow solid in quantitative yield (2.6
g); .sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 2.7 (3H, s), 7.8 (1H,
s).
[0226] Method E:
[0227] [2-(5-Chloro-thiazol-2-yl)-vinyl]-dimethyl-amine 111
[0228] A solution of 1-(5-Chloro-thiazol-2-yl)-ethanone (2.5 g) in
N,N'-dimethylformamide dimethyl acetal was refluxed for 6 hours.
The mixture was allowed to cool down and concentrated to a solid.
The residue was purified by flash chromatography (100% ethyl
acetate) to afford the sub-titled compound as an orange solid (1.5
g, 47%); .sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 3.0 (3H, s), 3.2
(3H, s), 6.0 (1H, br d), 7.7 (1H, s), 7.9 (1H, br d); MS (ES+)
217.1 (M+1).
[0229] Method F:
[0230]
[4-(5-Chloro-thiazol-2-yl)-pyrimidin-2-yl]-(3,4,5-trimethoxy-phenyl-
)-amine 112
[0231] To a solution of
[2-(5-Chloro-thiazol-2-yl)-vinyl]-dimethyl-amine (450 mg) in
isopropanol (10 ml) was added N-(3,4,5 trimethoxyphenyl)guanidinium
nitrate (560 mg) (prepared using a procedure similar to that
described in WO9719065) and sodium hydroxide (80 mg). The resulting
mixture was heated to reflux for 6 hours, then cooled to ambient
and concentrated. The mixture was diluted with water (20 ml) and
extracted with ethylacetate (20 ml), the organic phase was removed,
washed with water, brine, dried (magnesium sulfate) and
concentrated. The residue was purified by flash chromatography (30%
ethylacetate/petroleum ether) to afford the sub-titled compound as
an orange solid (260 mg, 35%); IR (solid) 1570, 1508, 1453, 1422
cm.sup.-1; .sup.1H NMR (400 Mhz, CDCl.sub.S) .delta. 3.8 (3H, s),
3.95 (6H, s), 7.15 (1H, s), 7.50 (1H, m), 7.75 (1H, s), 8.6 (1H,
d); MS (ES+) 379.2 (M+1), (ES-) 377.2 (M-1).
[0232] Method G
[0233]
[4-(5-piperazin-1-yl-thiazol-2-yl)-pyrimidin-2-yl]-(3,4,5-trimethox-
y-phenyl)-amine 113
[0234] To solution of
[4-(5-Chloro-thiazol-2-yl)-pyrimidin-2-yl]-(3,4,5-tr-
imethoxy-phenyl)-amine (150 mg) in dimethylsulfoxide (2 ml) was
added piperazine (300 mg). The mixture was heated to 100.degree. C.
for 5 hours then allowed to cool and concentrated under high vacuum
to an oil. The residue was purified by HPLC with 0.1% TFA/water
acetonitrile as eluant to afford the sub-titled compound as an
yellow solid (40 mg, 25%); IR (solid) 1567, 1504, 1432, 1411
cm.sup.-1; .sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 1.3-1.5 (1H,
br s), 3.1 (4H, s), 3.25 (4H, s), 3.85 (3H, s), 3.95 (6H, s), 7.05
(1H, s), 7.15 (1H, s), 7.19 (1H, s), 7.40 (1H, m), 8.6 (1H, d); MS
(ES+) 429.3 (M+1), (ES-) 427.3 (M-1).
Example 11
N'{2-[2-(3,5-Dimethyl-phenylamino)-pyrimidin-4-yl]-thiazol-5-yl}-ethane-1,-
2-diamine
[0235] 114
[0236] This compound was prepared using procedures similar to those
described in methods A-G. N-(3,5 dimethylphenyl) guanidinium
nitrate was prepared using a procedure similar to that described in
WO9719065. The product was isolated as a yellow solid after
purification by HPLC with 0.1% TFA/water acetonitrile as eluant (35
mg, 45% last step); IR (solid) 1622, 1565, 1455, 1332 cm.sup.-1;
.sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 1.3 (2H, br s), 2.5 (6H,
s), 3.0 (2H, s), 3.55 (2H, s), 6.7-6.8 (2H, m), 7.25 (1H, s), 7.35
(1H, s), 7.55 (1H, d), 8.35 (1H, s), 8.55 (1H, d); MS (ES+) 341.3
(M+1), (ES-) 339.3 (M-1).
Example 12
[4-(5-piperazin-1-yl-thiazol-2-yl)-pyrimidin-2-yl]-(3,5
dimethyl-phenyl)-amine
[0237] 115
[0238] Method H:
[0239] 5-Bromo-2-(1,1-dimethoxy-ethyl)-thiazole 116
[0240] To a cooled (-78.degree. C.) solution of
2-(1,1-Dimethoxy-ethyl)-th- iazole_(5.5 g) in THF (100 ml) was
added n-butyllithium (10 ml of 2.5M solution in hexanes) over 5
minutes. The resulting mixture was stirred for 30 minutes at
-78.degree. C., then a solution of carbon tetrabromide (11 g) in
THF (40 ml) was added dropwise over 5 minutes. The resulting
mixture was stirred for 30 minutes at -78.degree. C., then allowed
to warm up to 0.degree. C. and quenched with saturated ammonium
chloride solution. The mixture was concentrated to remove the THF,
diluted with water (100 ml) and extracted with diethyl ether (100
ml). The organic phase was removed, washed with water and brine,
dried (magnesium sulfate), filtered and concentrated. The residue
was purified by flash chromatography (5% ethyl acetate/petroleum
ether) to afford the sub-titled compound as a orange oil (5.7 g,
71%); .sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 1.70 (3H, s), 3.25
(6H, s), 7.7 (1H, s); MS (ES+) 252 (MBr.sup.79+1), 222 (M-31,
OCH.sub.3).
[0241] 1-(5-Bromo-thiazol-2-yl)-ethanone 117
[0242] This compound was prepared using a procedure similar to that
described in method D. The product was isolated as a yellow solid
(100% last step); .sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 2.7
(6H, s), 7.9 (1H, s).
[0243] [4-(5-piperazin-1-yl-thiazol-2-yl)-pyrimidin-2-yl]-(3,5
dimethyl-phenyl)-amine 118
[0244] This compound was prepared from
1-(5-Bromo-thiazol-2-yl)-ethanone (prepared as described above) and
N-(3,5 dimethylphenyl) guanidinium nitrate (prepared using a
procedure similar to that described in WO9719065) using procedures
similar to those described in methods E-G. The product was isolated
as a yellow solid (31% last step); .sup.1H NMR (400 Mhz,
CDCl.sub.3) 2.35 (6H, s), 3.05 (4H, s), 3.25 (4H, s), 6.75 (1H, s),
7.05 (1H, s), 7.37 (3H, m), 8.45 (1H, d), 8.55 (1H, d); MS (ES+)
367.3 (M+1), (ES-) 365.3 (M-1).
Example 13
(3,5-Dimethyl-phenyl)-[4-(5-piperidin-1-yl-thiazol-2-yl)-pyrimidin-2-yl]-a-
mine
[0245] 119
[0246] Method I
[0247] 1-(5-Piperidin-1-yl-thiazol-2-yl)-ethanone 120
[0248] To a solution of 1-(5-Bromo-thiazol-2-yl)-ethanone (prepared
as described above) (250 mg) in dimethylsulfoxide (3 ml) was added
piperidine (0.3 ml). The mixture was heated to 50.degree. C.
overnight, concentrated to an oil and the residue was purified by
flash chromatography (30% ethylacetate/petroleum ether) to afford
the sub-titled compound as an yellow solid (170 mg, 68%); .sup.1H
NMR (400 Mhz, CDCl.sub.3) .delta. 1.6-1.8 (6H, m), 2.6 (3H, s),
3.25-3.35 (4H, m), 7.05 (1H, s); MS (ES+) 211.1 (M+1).
[0249]
(3,5-Dimethyl-phenyl)-[4-(5-piperidin-1-yl-thiazol-2-yl)-pyrimidin--
2-yl]-amine 121
[0250] This compound was prepared from
1-(5-Piperidin-1-yl-thiazol-2-yl)-e- thanone (prepared as described
in method I) and N-(3,5 dimethylphenyl) guanidinium nitrate
(prepared using a procedure similar to that described in WO9719065)
using procedures similar to those described in methods E-F. The
product was isolated as a yellow solid (40% last step); IR (solid)
1561, 1474, 1407, 1244 cm.sup.-1; .sup.1H NMR (400 Mhz, CDCl.sub.3)
.delta. 1.6-1.7 (2H, m), 1.7-1.8 (4H, s), 2.4 (6H, s), 3.25-3.35
(4H, s), 6.75 (1H, s), 7.05 (1H, s), 7.1 (1H, s), 7.4 (2H, s), 7.5
(1H, m), 8.45 (1H, s); MS (ES+) 366.3 (M+1), (ES-) 364.3 (M-1).
Example 14
[4-(5-Dimethylamino-thiazol-2-yl)-pyrimidin-2-yl]-(3,5-dimethyl-phenyl)-am-
ine
[0251] 122
[0252] This compound was prepared from
1-(5-Dimethylamino-thiazol-2-yl)-et- hanone (prepared from
dimethylamine and 1-(5-Bromo-thiazol-2-yl)-ethanone in a procedure
similar to that described in method I) and N-(3,5 dimethylphenyl)
guanidinium nitrate (prepared using a procedure similar to that
described in WO9719065) using procedures similar to those described
in methods E-F. The product was isolated as a yellow solid (40%
last step); IR (solid) 1738, 1365, 1217, cm.sup.-1; .sup.1H NMR
(400 Mhz, CDCl.sub.3) .delta. 2.35 (6H, s), 3.1 (6H, s), 6.75 (1H,
s), 7.00 (1H, s), 7.37 (1H, s), 7.4 (2H, s), 8.45 (1H, d);); MS
(ES+) 326.2 (M+1), (ES-) 324.2 (M-1).
Example 15
(4-Benzothiazol-2-yl-pyrimidin-2-yl)-(3,5-dimethyl-phenyl)-amine
[0253] 123
[0254] Method A:
[0255] 1-Benzothiazol-2-yl-ethanone 124
[0256] Butyllithium (10.2 mL, 16.3 mmol, 1.6 M, 1.1 Eq) was added
dropwise to a stirred solution of benzothiazole (1.6 mL, 14.8 mmol,
1.0 Eq) in anhydrous THF (15 mL) at -78.degree. C. under nitrogen.
The resultant solution was stirred at -78.degree. C. for one hour.
N-Methoxy-N-methylacetamide (1.7 mL, 16.3 mmol, 1.1 Eq) was added
in one portion and the reaction stirred at -78.degree. C. for 3
hours. The resultant solution was allowed to warm to room
temperature overnight. The reaction was quenched by the addition of
1M HCl (10 mL) and extracted with ethyl acetate (3.times.15 mL).
The combined organic extracts were dried over solid MgSO.sub.4 and
filtered. The filtrate was concentrated under reduced pressure and
purified by column chromatography (10% ethyl acetate in hexanes) to
give the title compound as a yellow solid (1.0 g, 39% yield):
.sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 2.85 (3H, s), 7.54-7.62
(2H, m), 8.01 (1H, d), 8.21 (1H, d); MS: ES+ 178.0 (100%).
[0257] Method B:
[0258] 1-Benzothiazol-2-yl-3-dimethylamino-propenone 125
[0259] A solution of 1-Benzothiazol-2-yl-ethanone (1.0 g, 5.7 mmol,
1.0 Eq.) and dimethylformamide-dimethylacetal (2.4 mL, 17.7 mmol,
3.1 Eq.) in anhydrous THF (4 mL) was heated at reflux overnight.
The resultant red solution was cooled to room temperature and the
solvent removed in vacuo to give the title compound as a red solid
(1.3 g, 98% yield) that was used without further purification:
.sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 3.07 (3H, s), 3.25 (3H,
s), 6.37 (1H, br d), 7.42-7.55 (2H, m), 7.99 (1H, d), 8.12 (1H, d);
MS: ES+ 233.1 (100%).
[0260] Method C:
[0261]
(4-Benzothiazol-2-yl-pyrimidin-2-yl)-(3,5-dimethyl-phenyl)-amine
126
[0262] 1-Benzothiazol-2-yl-3-dimethylamino-propenone (348 mg, 1.5
mmol, 1 eq.), 3,5-dimethylphenylguanidine nitrate (prepared using a
procedure similar to that described in WO9719065) (339 mg, 1.5
mmol, 1 eq.) and sodium hydroxide (66 mg, 1.65 mmol, 1.1 eq.) were
suspended in isopropanol (15 mL) and the mixture was stirred at
reflux overnight. The resulting dark suspension was allowed to cool
to room temperature and diluted with water (10 mL). The solid
precipitate was isolated by filtration and washed sequentially with
water (2.times.5 mL), isopropanol (2.times.5 mL) and pentane
(2.times.5 mL) and then dried for 3 hours at 40C to give yellow
solid (351 mg, 70% yield): Mp 217-219.degree. C.; .sup.1H NMR (400
Mhz, CDCl.sub.3) .delta. 2.31 (6H, s), 6.68 (1H, s), 7.51-7.64 (5H,
m), 8.26 (1H, d), 8.27 (1H, d), 9.86 (1H, br s); IR (solid):
16.29.0, 15.67.6, 1444.7 cm.sup.-1; MS: ES+ 333.18 (100%),
ES-331.20 (50%), 165.04 (100%).
Example 16
2-(3,5-dimethylanilino)-4-(4,5-dimethylthiazolo)-pyrimidine
[0263] 127
[0264] Method D:
[0265] 2-Acetyl-4,5-dimethylthiazole 128
[0266] A solution of 4,5-dimethylthiazole (2.0 g, 17.67 mmol, 1
eq.) in dry diethyl ether (20 mL) was added slowly dropwise, over
approximately 30 minutes, to a solution of butyllithium (7.8 mL,
19.44 mmol, 2.5M, 1.1 eq.) in dry diethyl ether (20 mL) at
-70.degree. C. The resultant solution was stirred at -70.degree. C.
for 30 minutes, -30.degree. C. for 20 minutes and then re-cooled to
-70.degree. C. Dry ethyl acetate (3.11 g, 3.5 mL, 35.34 mmol, 2
eq.) was added in one portion to the deep red solution and the
cooling bath was removed. After 50 minutes stirring at room
temperature the reaction mixture was poured into saturated
NaHSO.sub.4 and extracted with ethyl acetate (3.times.50 mL). The
combined organic extracts were washed with saturated
Na.sub.2CO.sub.3 (1.times.50 mL), brine (1.times.50 mL), dried over
solid Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated
under reduced pressure and the resultant greenish, mobile oil was
purified by column chromatography (15% ethyl acetate in hexanes) on
silica gel giving a yellow oil (1.81 g, 66% yield): .sup.1H (400
Mhz, CDCl.sub.3) .delta. 2.4(3H, s), 2.5(3H, s), 2.7(3H, s).
[0267] 2-(3,5-dimethylanilino)-4-(4,5-dimethylthiazolo)-pyrimidine
129
[0268] This compound was prepared using method D and procedures
similar to those described in methods B-C. The product was obtained
as an orange solid (183.9 mg, 62% yield): Mp. 177-179.degree. C.;
.sup.1H (400 Mhz, DMSO) .delta. 2.3(6H, s), 2.4(3H, s), 2.45(3H,
s), 6.6-6.7(1H, s), 7.3-7.4(1H, m), 7.5(2H, s), 8.6(1H, m),
9.6-9.7(1H, s); IR (solid): 1532.1, 1532.9, 1568.1, 1586.0, 1615.1
cm.sup.-1; MS: ES+ 311.1(100%), 312.1(50%), 313.1(20%),
ES-309.(30%).
Example 17
Methyl Substituted Thiazoles
[0269] 2-Chloro-4-(5-methyl-2'thiazolyl)pyrimidine: 130
[0270] To a cooled (-78.degree. C.) solution of nBuLi (2.5M
hexanes, 4.1 ml) in diethyl ether (10 ml) was added a solution of
5-methylthiazole (1 g) in diethyl ether (10 ml) dropwise over 30
minutes. The resulting mixture was stirred for 30 minutes, then
warmed to -30.degree. C. and stirred for an additional 15 minutes.
A solution of 2-chloropyrimidine (1.1 g) in diethyl ether (25 ml)
was then added dropwise. The solution was stirred at -30.degree. C.
for 30 minutes, then warmed to 0.degree. C. and stirred until the
reaction was complete. Water (0.2 ml) in TBF (2.5 ml) was then
added followed by DDQ (2.27 g) in THF (10 ml) and the mixture
stirred at 0.degree. C. for 15 minutes. 3M sodium hydroxide (10 ml)
was then added and the mixture stirred for an additional 5
minutes.
[0271] The mixture was then diluted with ethyl acetate and the
organic phase removed. The aqueous phase was further extracted with
ethyl acetate. The combined organic phases were washed with water,
then brine, dried (magnesium sulfate), filtered and concentrated to
give a crude product. This was further purified by triturating with
hexanes. The title compound was obtained as a solid (1 g, 47%
yield); .sup.1H NMR (400 Mhz, CDCl.sub.3) .delta. 2.61 (3H, s),
7.70 (1H, s), 8.00 (1H, d), 8.69 (1H, d).
[0272] General procedure for the reaction of
2-Chloro-4-(5-methyl-2'thiazo- lyl)pyrimidine with amines. 131
[0273] A mixture of 2-Chloro-4-(5-methyl-2'thiazolyl)pyrimidine
(100 mg) and the appropriate amine (3 equivalents) in n-butanol (5
ml) was heated at 85.degree. C. for 18-24 hours. The mixture was
then cooled to ambient. The mixture was then concentrated and the
crude dissolved in dichloromethane. The organic solution was washed
with saturated sodium hydrogen carbonate, dried (magnesium
sulfate), filtered and concentrated. The product was obtained by
triturating with hexanes. Further purification by preparative HPLC
was carried out if required.
1TABLE 2 Exemplary NMR data for certain compounds of the invention
(compound numbers refer to those numbers depicted in Table 1) are
depicted below in Table 2: Compound Number H.sup.1 NMR I-88 H.sup.1
NMR MeOD 8.6 d(1H), 8.1 s(1H), 7.45 d(1H), 7.4 s(2H), 6.7 s(1H),
4.6 s(2H), 4.8 m(4H), 2.3 s(6H), 1.95 m(2H), 1.85 m(2H) I-87
H.sup.1 NMR MeOD 8.6 d(1H), 8.2 s(1H), 7.45 d(1H), 7.4 s(1H), 6.8
s(1H), 3.9 t(2H), 3.75 t(1H), 3.0 s(2H), 2.3 s (6H), 2.85 t(1H)
I-86 H.sup.1 NMR MeOD 8.6 d(1H), 8.15 s(1H), 7.45 d(1H), 7.4 s(1H),
6.7 s(1H), 5 d(1H), 4.8 d(1H), 4.8 dd(1H), 4.75 m(1H), 4.55 m(1H),
4.4 m(1H), 2.3 s(6H), 2.25 m(1H), 2.1 m(1H), 2.0 m(1H), 1.9 m(1H)
I-48 H.sup.1 NMR MeOD 8.55 d(1H), 8.2 s(1H), 8.45 d(1H), 7.35
s(2H), 6.7 s(1H), 5.75 s(2H), 3.1 m(4H), 2.35 s(6H), 2.15 m(2H),
1.35 m(2H) I-46 H.sup.1 NMR MeOD 8.55 d(1H), 8.15 s(1H), 8.5 d(1H),
7.35 s(2H), 6.7 s(1H), 5.75 s(2H), 4.1-3.7 bs(4H), 3.5-3.3 bs(4H),
2.7 s(2H), 2.35 s(4H) I-47 H.sup.1 NMR MeOD 8.5 d(1H), 7.9 s(1H),
7.5 d(1H), 7.35 s(2H), 6.7 s(1H)4.0 s(2H), 3.6-3.5 bs(2H), 3.2
q(2H), 3.15-3.0 bs(4H), 2.5 bs (2H), 2.35 s(6H), 1.3 t(3H) I-44
H.sup.1 NMR MeOD 8.55 d(1H), 8.1 s(1H), 7.55 d(1H), 7.3 s(2H), 6.7
s(1H), 4.75 s(2H), 2.9 s(6H), 2.3 s(6H)
[0274] B) Biological Data:
Example 1
SYK Inhibition Assay
[0275] Compounds were screened for their ability to inhibit SYK
using a standard coupled enzyme assay (Fox et al., Protein Sci.
1998, 7, 2249). Reactions were carried out in 100 mM HEPES (pH
7.5), 10 mM MgCl.sub.2, 25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final
substrate concentrations in the assay were 200 .mu.M ATP (Sigma
chemical Co.) and 4 .mu.M poly Gly-Tyr peptide (Sigma Chemical
Co.). Assays were carried out at 30.degree. C. and 200 nM SYK.
Final concentrations of the components of the coupled enzyme system
were 2.5 mM phosphoenolpyruvate, 300 .mu.M NADH, 30 .mu.g/ml
pyruvate kinase and 10 .mu.g/ml lactate dehydrogenase.
[0276] An assay stock buffer solution was prepared containing all
of the reagents listed above, with the exception of SYK, DTT, and
the test compound of interest of the present invention. 56 .mu.l of
the test reaction was placed in a 96 well plate followed by the
addition of 1 .mu.l of 2 mM DMSO stock containing the test compound
of the present invnetion (final compound concentration 30 .mu.M).
The plate was pre-incubated for .about.10 minutes at 30.degree. C.
and the reaction initiated by the addition of 10 .mu.l of enzyme
(final concentration 25 nM). Rates of reaction were obtained using
a BiORad Ultramark plate reader (Hercules, Calif.) over a 5 minute
read time at 30.degree. C., and K.sub.i values for the compounds of
the present invention were determined according to standard
methods.
[0277] Compounds of the invention are useful as inhibitors of SYK.
The following compounds exhibit K.sub.i values of 5.0 .mu.M or
less: I-1, I-2, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-12, I-14,
I-15, I-16, I-17, I-18, I-19, I-20, I-22, I-23, I-26, I-27, I-28,
I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-41,
I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52,
I-58, I-63, I-64, I-66, I-67, I-70, I-71, I-72, I-73, I-74, I-75,
I-76, I-77, I-78, I-79, I-81, I-83, I-84, I-85, I-86, I-87, I-88,
I-89, I-90, I-91, I-92, I-93, I-94, I-95, I-97, I-100, I-102,
I-103, I-106, I-109, I-110, I-111, I-112, I-114, I-115, I-116,
I-118, I-119, I-120, I-121, I-122, I-123, I-124, I-125, I-126,
I-127, I-128, I-130, I-131, I-134, I-135, I-136, I-137, I-138,
I-140, I-141, I-142, I-143, I-144, I-145, I-146, I-149, I-150,
I-151, I-152, I-153, I-154, I-155, I-156, and I-157.
Example 2
ZAP-70 Inhibition Assay
[0278] Compounds were screened for their ability to inhibit ZAP-70
using a standard coupled enzyme assay (Fox et al., Protein Sci.
1998, 7, 2249). Assays were carried out in a mixture of 100 mM
HEPES (pH 7.5), 10 mM MgCl.sub.2, 25 mM NaCl, 2 mM DTT and 3% DMSO.
Final substrate concentrations in the assay were 100 .mu.M ATP
(Sigma Chemicals) and 20 .mu.M peptide (poly-4EY, Sigma Chemicals).
Assays were carried out at 30.degree. C. and 60 nM ZAP-70. Final
concentrations of the components of the coupled enzyme system were
2.5 mM phosphoenolpyruvate, 300 .mu.M NADH, 30 .mu.g/ml pyruvate
kinase and 10 .mu.g/ml lactate dehydrogenase.
[0279] An assay stock buffer solution was prepared containing all
of the reagents listed above, with the exception of ZAP-70 and the
test compound of interest of the present invention. 55 .mu.l of the
stock solution was placed in a 96 well plate followed by addition
of 2 .mu.l of DMSO stock containing serial dilutions of the test
compound of the present invention (typically starting from a final
concentration of 15 .mu.M). The plate was preincubated for 10
minutes at 30.degree. C. and the reaction initiated by addition of
10 .mu.l of enzyme (final concentration 60 nM). Initial reaction
rates were determined with a Molecular Devices SpectraMax Plus
plate reader over a 15 minute time course. K.sub.i data was
calculated from non-linear regression analysis using the Prism
software package (GraphPad Prism version 3.0a for Macintosh,
GraphPad Software, San Diego Calif., USA).
[0280] Compounds of the invention are useful as inhibitors of
ZAP-70. The following compounds exhibit K.sub.i values of 5.0 .mu.M
or less: I-1, I-2, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-12, I-14,
I-15, I-16, I-17, I-18, I-19, I-20, I-22, I-23, I-26, I-27, I-28,
I-29, I-30, I-31, I-32, I-34, I-35, I-36, I-37, I-38, I-41, I-42,
I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-63,
I-64, I-66, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78,
I-79, I-81, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91,
I-92, I-93, I-94, I-95, I-97, I-100, I-102, I-103, I-106, I-109,
I-110, I-111, I-112, I-114, I-115, I-116, I-118, I-119, I-120,
I-121, I-122, I-123, I-124, I-125, I-127, I-128, I-130, I-131,
I-134, I-135, I-136, I-137, I-138, I-140, I-141, I-142, I-143,
I-144, I-145, I-146, I-149, I-150, I-152, I-153, I-154, I-155,
I-156, and 1-157.
[0281] While a number of embodiments of this invention have been
described, it is apparent that the basic examples described herein
may be altered to provide other embodiments that utilize the
compounds and methods of this invention. Therefore, it will be
appreciated that the scope of this invention is to be defined by
the appended claims rather than by the specific embodiments that
have been represented by way of example.
* * * * *